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Kefalas G, Priya A, Astori A, Persaud A, Jing L, Sydor AM, Yao HHY, Warner N, Zhang Y, Brumell JH, Muise AM, Sari S, Su HC, Lenardo MJ, Kahr WHA, Raught B, Rotin D. The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy. Nat Commun 2025; 16:2682. [PMID: 40102426 PMCID: PMC11920435 DOI: 10.1038/s41467-025-57944-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 03/03/2025] [Indexed: 03/20/2025] Open
Abstract
The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW(n)-HECT domains, regulates protein trafficking. We recently described a primate-specific Nedd4-1 splice isoform with an extended N-terminus replacing the C2 domain, called Nedd4-1(NE). Here, we show that while canonical Nedd4-1 is primarily localized to the cytosol, Nedd4-1(NE) localizes to late endosomes. This localization is mediated by the NE region, is dependent on amino acid availability, is independent of mTORC1, and is inhibited by the autophagy inducer IKKβ. We further demonstrate that VPS16B, which regulates late endosome to lysosome maturation, is a unique Nedd4-1(NE) substrate that co-localizes with Nedd4-1(NE) in the presence of nutrients. Importantly, a potentially pathogenic homozygous variant identified in the NE region (E70Q) of a patient with lymphangiectasia and protein-losing enteropathy leads to reduced VPS16B ubiquitination by Nedd4-1(NE). Finally, we report that Nedd4-1(NE) inhibits autophagy, likely by disrupting late endosome to autophagosome maturation. This work identified an mTORC1-independent, IKK-driven mechanism to regulate Nedd4-1(NE) localization to late endosomes in primates in response to nutrient availability, and uncovered suppression of autophagy by this ubiquitin ligase.
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Affiliation(s)
- G Kefalas
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - A Priya
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - A Astori
- Princess Margaret Cancer Centre, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - A Persaud
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - L Jing
- Princess Margaret Cancer Centre, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - A M Sydor
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - H H Y Yao
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - N Warner
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Y Zhang
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - J H Brumell
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - A M Muise
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - S Sari
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Gazi University, Ankara, Turkey
| | - H C Su
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - M J Lenardo
- Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - W H A Kahr
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - B Raught
- Princess Margaret Cancer Centre, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - D Rotin
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
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Yao HHY, Kahr WHA. Molecular basis of platelet granule defects. J Thromb Haemost 2025; 23:381-393. [PMID: 39617187 DOI: 10.1016/j.jtha.2024.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 01/02/2025]
Abstract
Platelets are small, discoid, anucleate blood cells that play key roles in clotting and other functions involved in health and disease. Platelets are derived from bone marrow-resident megakaryocytes, which undergo a complex developmental process where they increase dramatically in size and produce an abundance of organelles destined for platelets. These organelles include mitochondria, lysosomes, peroxisomes, and 2 unique types of secretory organelles: α- and dense (δ-) granules. δ-Granules contain small molecules, including adenosine triphosphate, adenosine diphosphate, serotonin, and ions, such as calcium and zinc (Ca2+ and Zn2+). α-Granules contain a variety of cargo proteins, which, when secreted by activated platelets, are involved in processes such as hemostasis (eg, fibrinogen and von Willebrand factor), angiogenesis, inflammation, and wound healing. Investigations of patients with inherited conditions resulting in decreased/abnormal platelet secretory granules have led to the identification of proteins, protein complexes, and cellular processes involved in their production by megakaryocytes. Notably, studies of ARPC1B deficiency, Hermansky-Pudlak, and Chediak-Higashi syndromes have linked several genes/proteins to δ-granule biogenesis. Studies of multisystemic arthrogryposis, renal dysfunction, and cholestasis syndrome revealed the requirement of 2 proteins, VPS33B and VPS16B, in α-granule formation. Identification of the genetic cause of gray platelet syndrome established that NBEAL2 is an additional protein needed for α-granule cargo retention. These discoveries enabled studies using animal models, cell culture, and molecular analysis to gain insights into the roles of proteins and cellular processes involved in platelet secretory granule production, which are discussed in this review.
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Affiliation(s)
- Helen H Y Yao
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Walter H A Kahr
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; Division of Haematology/Oncology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
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Perez SM, Augustineli HS, Marcello MR. Utilizing C. elegans Spermatogenesis and Fertilization Mutants as a Model for Human Disease. J Dev Biol 2025; 13:4. [PMID: 39982357 PMCID: PMC11843878 DOI: 10.3390/jdb13010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/10/2025] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
The nematode C. elegans is a proven model for identifying genes involved in human disease, and the study of C. elegans reproduction, specifically spermatogenesis and fertilization, has led to significant contributions to our understanding of cellular function. Approximately 70 genes have been identified in C. elegans that control spermatogenesis and fertilization (spe and fer mutants). This review focuses on eight genes that have human orthologs with known pathogenic phenotypes. Using C. elegans to study these genes has led to critical developments in our understanding of protein domain function and human disease, including understanding the role of OTOF (the ortholog of C. elegans fer-1) in hearing loss, the contribution of the spe-39 ortholog VIPAS39 in vacuolar protein sorting, and the overlapping functions of spe-26 and KLHL10 in spermatogenesis. We discuss the cellular function of both the C. elegans genes and their human orthologs and the impact that C. elegans mutants and human variants have on cellular function and physiology. Utilizing C. elegans to understand the function of the genes reviewed here, and additional understudied and undiscovered genes, represents a unique opportunity to understand the function of variants that could lead to better disease diagnosis and clinical decision making.
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Kafol J, Gnidovec Strazisar B, Drole Torkar A, Homan M, Bertok S, Mlinaric M, Sikonja J, Kovač J, Perkovic Benedik M, Kersnik Levart T, Zerjav Tansek M, Praprotnik M, Battelino T, Debeljak M, Groselj U. VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome-case report and systematic review. Orphanet J Rare Dis 2024; 19:496. [PMID: 39736737 PMCID: PMC11684101 DOI: 10.1186/s13023-024-03486-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 11/29/2024] [Indexed: 01/01/2025] Open
Abstract
BACKGROUND Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, a rare autosomal recessive disorder, exhibits genetic heterogeneity with the VIPAS39 gene pathological variants being a distinct contributor. RESULTS We present two related patients from Kosovo, describing the clinical, genetic, and therapeutic aspects of the syndrome. The identified novel VIPAS39 pathological variants (c.762G > A; c.1064_1082delinsAGTG) emphasize the complex phenotypic expression of ARC syndrome. A systematic literature review identified 8 VIPAS39-related ARC cases with notable variability in clinical features. Prognostically, patients fell into severe and milder groups, with some reaching adolescence. Our report aligns with others noting milder ARC courses and emphasizes the value of genetic testing, especially in atypical presentations. Challenges included incomplete literature data, early mortality affecting diagnostic workup, and limited VIPAS39-related ARC cases. Comparisons with the more prevalent VPS33B pathological variants revealed no distinct clinical differences. CONCLUSION Our study expands understanding of ARC syndrome, highlighting its genetic diversity and clinical variability. Milder presentations underscore diagnostic challenges and the potential prevalence of undiagnosed cases. Increased awareness and comprehensive genetic testing are crucial for early and accurate diagnosis.
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Affiliation(s)
- Jan Kafol
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Barbara Gnidovec Strazisar
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Department of Pediatrics, General Hospital Celje, Celje, Slovenia
| | - Ana Drole Torkar
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Matjaz Homan
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Sara Bertok
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Matej Mlinaric
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Jaka Sikonja
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Jernej Kovač
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Mirjana Perkovic Benedik
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Child, Adolescent and Developmental Neurology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tanja Kersnik Levart
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Nephrology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Mojca Zerjav Tansek
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Marina Praprotnik
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department for Pulmonary Diseases, University Children's Hospital Ljubljana, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia
| | - Maruša Debeljak
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Urh Groselj
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
- Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000, Ljubljana, Slovenia.
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More KJ, Kaufman JGG, Dacks JB, Manna PT. Evolutionary origins of the lysosome-related organelle sorting machinery reveal ancient homology in post-endosome trafficking pathways. Proc Natl Acad Sci U S A 2024; 121:e2403601121. [PMID: 39418309 PMCID: PMC11513930 DOI: 10.1073/pnas.2403601121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/22/2024] [Indexed: 10/19/2024] Open
Abstract
The major organelles of the endomembrane system were in place by the time of the last eukaryotic common ancestor (LECA) (~1.5 billion years ago). Their acquisitions were defining milestones during eukaryogenesis. Comparative cell biology and evolutionary analyses show multiple instances of homology in the protein machinery controlling distinct interorganelle trafficking routes. Resolving these homologous relationships allows us to explore processes underlying the emergence of additional, distinct cellular compartments, infer ancestral states predating LECA, and explore the process of eukaryogenesis itself. Here, we undertake a molecular evolutionary analysis (including providing a transcriptome of the jakobid flagellate Reclinomonas americana), exploring the origins of the machinery responsible for the biogenesis of lysosome-related organelles (LROs), the Biogenesis of LRO Complexes (BLOCs 1,2, and 3). This pathway has been studied only in animals and is not considered a feature of the basic eukaryotic cell plan. We show that this machinery is present across the eukaryotic tree of life and was likely in place prior to LECA, making it an underappreciated facet of eukaryotic cellular organisation. Moreover, we resolve multiple points of ancient homology between all three BLOCs and other post-endosomal retrograde trafficking machinery (BORC, CCZ1 and MON1 proteins, and an unexpected relationship with the "homotypic fusion and vacuole protein sorting" (HOPS) and "Class C core vacuole/endosomal tethering" (CORVET) complexes), offering a mechanistic and evolutionary unification of these trafficking pathways. Overall, this study provides a comprehensive account of the rise of the LROs biogenesis machinery from before the LECA to current eukaryotic diversity, integrating it into the larger mechanistic framework describing endomembrane evolution.
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Affiliation(s)
- Kiran J. More
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB T6G 2N8, Canada
- Department of Biological Sciences, University of Alberta, Edmonton, ABT6G 2N8, Canada
| | - Jonathan G. G. Kaufman
- Cambridge Institute for Medical Research, University of Cambridge, CambridgeCB2 0XY, United Kingdom
| | - Joel B. Dacks
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB T6G 2N8, Canada
- Department of Biological Sciences, University of Alberta, Edmonton, ABT6G 2N8, Canada
- Department of Genetics, Evolution, and Environment, Centre for Life’s Origin and Evolution, University College, LondonWC1E 6BT, United Kingdom
- Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice (Budweis)370 05, Czech Republic
| | - Paul T. Manna
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB T6G 2N8, Canada
- Department of Physiology, Gothenburg University, Gothenburg413 90, Sweden
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Szabó L, Pollio AR, Vogel GF. Intracellular Trafficking Defects in Congenital Intestinal and Hepatic Diseases. Traffic 2024; 25:e12954. [PMID: 39187475 DOI: 10.1111/tra.12954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/11/2024] [Accepted: 07/30/2024] [Indexed: 08/28/2024]
Abstract
Enterocytes and liver cells fulfill important metabolic and barrier functions and are responsible for crucial vectorial secretive and absorptive processes. To date, genetic diseases affecting metabolic enzymes or transmembrane transporters in the intestine and the liver are better comprehended than mutations affecting intracellular trafficking. In this review, we explore the emerging knowledge on intracellular trafficking defects and their clinical manifestations in both the intestine and the liver. We provide a detailed overview including more investigated diseases such as the canonical, variant and associated forms of microvillus inclusion disease, as well as recently described pathologies, highlighting the complexity and disease relevance of several trafficking pathways. We give examples of how intracellular trafficking hubs, such as the apical recycling endosome system, the trans-Golgi network, lysosomes, or the Golgi-to-endoplasmic reticulum transport are involved in the pathomechanism and lead to disease. Ultimately, understanding these processes could spark novel therapeutic approaches, which would greatly improve the quality of life of the affected patients.
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Affiliation(s)
- Luca Szabó
- Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Adam R Pollio
- Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Friedrich Vogel
- Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
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Walker E, Hayes W, Bockenhauer D. Inherited non-FGF23-mediated phosphaturic disorders: A kidney-centric review. Best Pract Res Clin Endocrinol Metab 2024; 38:101843. [PMID: 38042745 DOI: 10.1016/j.beem.2023.101843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2023]
Abstract
Phosphate is freely filtered by the glomerulus and reabsorbed exclusively in the proximal tubule by two key transporters, NaPiIIA and NaPiIIC, encoded by SLC34A1 and SLC34A3, respectively. Regulation of these transporters occurs primarily through the hormone FGF23 and, to a lesser degree, PTH. Consequently, inherited non-FGF23 mediated phosphaturic disorders are due to generalised proximal tubular dysfunction, loss-of-function variants in SLC34A1 or SLC34A3 or excess PTH signalling. The corresponding disorders are Renal Fanconi Syndrome, Infantile Hypercalcaemia type 2, Hereditary Hypophosphataemic Rickets with Hypercalciuria and Familial Hyperparathyroidism. Several inherited forms of Fanconi renotubular syndrome (FRTS) have also been described with the underlying genes encoding for GATM, EHHADH, HNF4A and NDUFAF6. Here, we will review their pathophysiology, clinical manifestations and the implications for treatment from a kidney-centric perspective, focussing on those disorders caused by dysfunction of renal phosphate transporters. Moreover, we will highlight specific genetic aspects, as the availability of large population genetic databases has raised doubts about some of the originally proposed gene-disease associations concerning phosphate transporters or their associated proteins.
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Affiliation(s)
- Emma Walker
- Nephrology Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Wesley Hayes
- Nephrology Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Detlef Bockenhauer
- Nephrology Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Department of Renal Medicine, University College London, London, UK.
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Guo RJ, Cao YF, Li EM, Xu LY. Multiple functions and dual characteristics of RAB11A in cancers. Biochim Biophys Acta Rev Cancer 2023; 1878:188966. [PMID: 37657681 DOI: 10.1016/j.bbcan.2023.188966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/05/2023] [Accepted: 08/05/2023] [Indexed: 09/03/2023]
Abstract
Vesicle trafficking is an unceasing and elaborate cellular process that functions in material transport and information delivery. Recent studies have identified the small GTPase, Ras-related protein in brain 11A (RAB11A), as a key regulator in this process. Aberrant RAB11A expression has been reported in several types of cancers, suggesting the important functions and characteristics of RAB11A in cancer. These discoveries are of great significance because therapeutic strategies based on the physiological and pathological status of RAB11A might make cancer treatment more effective, as the molecular mechanisms of cancer development have not been completely revealed. However, these studies on RAB11A have not been reviewed and discussed specifically. Therefore, we summarize and discuss the recent findings of RAB11A involvement in different biological processes, including endocytic recycling regulation, receptors and adhesion molecules recycling, exosome secretion, phagophore formation and cytokinesis, as well as regulatory mechanisms in several tumor types. Moreover, contradictory effects of RAB11A have also been observed in different types of cancers, implying the dual characteristics of RAB11A in cancer, which are either oncogenic or tumor-suppressive. This review on the functions and characteristics of RAB11A highlights the value of RAB11A in inducing multiple important phenotypes based on vesicle trafficking and therefore will offer insights for future studies to reveal the molecular mechanisms, clinical significance, and therapeutic targeting of RAB11A in different cancers.
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Affiliation(s)
- Rui-Jian Guo
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China
| | - Yu-Fei Cao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
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Shimizu N, Shiraishi H, Hanada T. Zebrafish as a Useful Model System for Human Liver Disease. Cells 2023; 12:2246. [PMID: 37759472 PMCID: PMC10526867 DOI: 10.3390/cells12182246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/31/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Liver diseases represent a significant global health challenge, thereby necessitating extensive research to understand their intricate complexities and to develop effective treatments. In this context, zebrafish (Danio rerio) have emerged as a valuable model organism for studying various aspects of liver disease. The zebrafish liver has striking similarities to the human liver in terms of structure, function, and regenerative capacity. Researchers have successfully induced liver damage in zebrafish using chemical toxins, genetic manipulation, and other methods, thereby allowing the study of disease mechanisms and the progression of liver disease. Zebrafish embryos or larvae, with their transparency and rapid development, provide a unique opportunity for high-throughput drug screening and the identification of potential therapeutics. This review highlights how research on zebrafish has provided valuable insights into the pathological mechanisms of human liver disease.
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Affiliation(s)
- Nobuyuki Shimizu
- Department of Cell Biology, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
| | | | - Toshikatsu Hanada
- Department of Cell Biology, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
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Picker SM, Parker G, Gissen P. Features of Congenital Arthrogryposis Due to Abnormalities in Collagen Homeostasis, a Scoping Review. Int J Mol Sci 2023; 24:13545. [PMID: 37686358 PMCID: PMC10487887 DOI: 10.3390/ijms241713545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Congenital arthrogryposis (CA) refers to the presence of multiple contractures at birth. It is a feature of several inherited syndromes, notable amongst them are disorders of collagen formation. This review aims to characterize disorders that directly or indirectly impact collagen structure and function leading to CA in search for common phenotypic or pathophysiological features, possible genotype-phenotype correlation, and potential novel treatment approaches based on a better understanding of the underlying pathomechanism. Nine genes, corresponding to five clinical phenotypes, were identified after a literature search. The most notable trend was the extreme phenotype variability. Clinical features across all syndromes ranged from subtle with minimal congenital contractures, to severe with multiple congenital contractures and extra-articular features including skin, respiratory, or other manifestations. Five of the identified genes were involved in the function of the Lysyl Hydroxylase 2 or 3 enzymes, which enable the hydroxylation and/or glycosylation of lysyl residues to allow the formation of the collagen superstructure. Whilst current treatment approaches are post-natal surgical correction, there are also potential in-utero therapies being developed. Cyclosporin A showed promise in treating collagen VI disorders although there is an associated risk of immunosuppression. The treatments that could be in the clinical trials soon are the splice correction therapies in collagen VI-related disorders.
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Affiliation(s)
| | - George Parker
- Newcastle University Medical School, Newcastle NE2 4HH, UK;
| | - Paul Gissen
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
- Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
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11
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Liu RJY, Al-Molieh Y, Chen SZ, Drobac M, Urban D, Chen CH, Yao HHY, Geng RSQ, Li L, Pluthero FG, Benlekbir S, Rubinstein JL, Kahr WHA. The Sec1/Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B. J Biol Chem 2023; 299:104718. [PMID: 37062417 DOI: 10.1016/j.jbc.2023.104718] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/03/2023] [Accepted: 04/07/2023] [Indexed: 04/18/2023] Open
Abstract
Loss of function variants of VPS33B and VIPAS39 (encoding VPS16B) are causative for arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, where early lethality of patients indicates that VPS33B and VPS16B play essential cellular roles. VPS33B is a member of the Sec1/Munc18 (SM) protein family, and thus thought to facilitate vesicular fusion via interaction with SNARE complexes, as does its paralog VPS33A in the homotypic fusion and vacuole sorting (HOPS) complex. VPS33B and VPS16B have been shown to associate, but little is known about the composition, structure or function of the VPS33B/VPS16B complex. We show here that human VPS33B/VPS16B is a high molecular weight complex, which we expressed in yeast to obtain material for structural, composition and stability analysis. Circular dichroism data indicate VPS33B/VPS16B has a well-folded α-helical secondary structure, for which size exclusion chromatography-multi angle light scattering revealed a MW of ∼315 kDa. Quantitative immunoblotting indicated the complex has a VPS33B:VPS16B ratio of 2:3. Expression of ARC syndrome-causing VPS33B missense variants showed that L30P disrupts complex formation, but not S243F or H344D. Truncated VPS16B containing amino acids 143-316 was sufficient to form a complex with VPS33B. Small angle X-ray scattering and negative staining electron microscopy revealed a two-lobed shape for VPS33B/VPS16B. Avidin tagging indicated that each lobe contains a VPS33B molecule, and they are oriented in opposite directions. From this we propose a structure for VPS33B/VPS16B that allows the copies of VPS33B at each end to interact with separate SNARE bundles and/or SNAREpins, plus their associated membrane components. Thus our observations reveal the only known potentially bidirectional SM protein complex.
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Affiliation(s)
- Richard J Y Liu
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Yusef Al-Molieh
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Shao Z Chen
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Marko Drobac
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Denisa Urban
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Chang H Chen
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Helen H Y Yao
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Ryan S Q Geng
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Ling Li
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Fred G Pluthero
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Samir Benlekbir
- Molecular Medicine Program, Research Institute, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - John L Rubinstein
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada; Molecular Medicine Program, Research Institute, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
| | - Walter H A Kahr
- Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada; Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada; Division of Haematology/Oncology, Department of Paediatrics, University of Toronto and The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
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12
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Fischer J, Hotz A, Komlosi K. Syndromic ichthyoses. MED GENET-BERLIN 2023; 35:23-32. [PMID: 38835422 PMCID: PMC10842576 DOI: 10.1515/medgen-2023-2006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are further defined on the basis of clinical and genetic features and can be divided into non-syndromic and syndromic forms. To date, mutations in more than 30 genes are known to result in various types of syndromic ichthyoses, which, in addition to mostly generalised scaling and hyperkeratosis of the skin, also show additional organ involvement. The syndromic ichthyoses are generally very rare and are classified based on the mode of inheritance, and can be further subdivided according to the predominant symptoms. In our review we provide a concise overview of the most prevalent syndromic forms of ichthyosis within each subgroup. We emphasize the importance of the clinical assessment of complex syndromes even in the era of genetic testing as a first-tier diagnostic and specifically the need to actively assess potential organ involvement in patients with ichthyosis, thereby enabling efficient diagnostic and therapeutic approaches and timely access to specialized centers for rare disorders of cornifications. As part of the Freiburg Center for Rare Diseases a Center for Cornification Disorders was recently established with collaboration of the Institute of Human Genetics and the Department of Dermatology. An early diagnosis of syndromes will be of direct benefit to the patient regarding interventional and therapeutic measures e. g. in syndromes with cardiac or metabolic involvement and allows informed reproductive options and access to prenatal and preimplantation genetic diagnosis in the family.
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Affiliation(s)
- Judith Fischer
- University of FreiburgFaculty of MedicineFreiburgDeutschland
| | - Alrun Hotz
- University of FreiburgFaculty of MedicineFreiburgDeutschland
| | - Katalin Komlosi
- University of FreiburgFaculty of MedicineFreiburgDeutschland
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13
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Abstract
Cargo delivery from one compartment to the next relies on the fusion of vesicles with different cellular organelles in a process that requires the concerted action of tethering factors. Although all tethers act to bridge vesicle membranes to mediate fusion, they form very diverse groups as they differ in composition, and in their overall architecture and size, as well as their protein interactome. However, their conserved function relies on a common design. Recent data on class C Vps complexes indicates that tethers play a significant role in membrane fusion beyond vesicle capturing. Furthermore, these studies provide additional mechanistic insights into membrane fusion events and reveal that tethers should be considered as key players of the fusion machinery. Moreover, the discovery of the novel tether FERARI complex has changed our understanding of cargo transport in the endosomal system as it has been shown to mediate 'kiss-and-run' vesicle-target membrane interactions. In this Cell Science at a Glance and the accompanying poster, we compare the structure of the coiled-coil and the multisubunit CATCHR and class C Vps tether families on the basis of their functional analogy. We discuss the mechanism of membrane fusion, and summarize how tethers capture vesicles, mediate membrane fusion at different cellular compartments and regulate cargo traffic.
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Affiliation(s)
| | - Anne Spang
- Biozentrum, University of Basel, 4056 Basel, Switzerland
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14
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Gutiérrez-Cerrajero C, Sprecher E, Paller AS, Akiyama M, Mazereeuw-Hautier J, Hernández-Martín A, González-Sarmiento R. Ichthyosis. Nat Rev Dis Primers 2023; 9:2. [PMID: 36658199 DOI: 10.1038/s41572-022-00412-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/02/2022] [Indexed: 01/20/2023]
Abstract
The ichthyoses are a large, heterogeneous group of skin cornification disorders. They can be inherited or acquired, and result in defective keratinocyte differentiation and abnormal epidermal barrier formation. The resultant skin barrier dysfunction leads to increased transepidermal water loss and inflammation. Disordered cornification is clinically characterized by skin scaling with various degrees of thickening, desquamation (peeling) and erythema (redness). Regardless of the type of ichthyosis, many patients suffer from itching, recurrent infections, sweating impairment (hypohidrosis) with heat intolerance, and diverse ocular, hearing and nutritional complications that should be monitored periodically. The characteristic clinical features are considered to be a homeostatic attempt to repair the skin barrier, but heterogeneous clinical presentation and imperfect phenotype-genotype correlation hinder diagnosis. An accurate molecular diagnosis is, however, crucial for predicting prognosis and providing appropriate genetic counselling. Most ichthyoses severely affect patient quality of life and, in severe forms, may cause considerable disability and even death. So far, treatment provides only symptomatic relief. It is lifelong, expensive, time-consuming, and often provides disappointing results. A better understanding of the molecular mechanisms that underlie these conditions is essential for designing pathogenesis-driven and patient-tailored innovative therapeutic solutions.
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Affiliation(s)
- Carlos Gutiérrez-Cerrajero
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Eli Sprecher
- Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amy S Paller
- Departments of Dermatology and Paediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | | | | | - Rogelio González-Sarmiento
- Department of Medicine, Faculty of Medicine, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
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15
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Scietti L, Forneris F. Modeling of Protein Complexes. Methods Mol Biol 2023; 2627:349-371. [PMID: 36959458 DOI: 10.1007/978-1-0716-2974-1_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
The recent advances in structural biology, combined with continuously increasing computational capabilities and development of advanced softwares, have drastically simplified the workflow for protein homology modeling. Modeling of individual proteins is nowadays quick and straightforward for a large variety of protein targets, thanks to guided pipelines relying on advanced computational tools and user-friendly interfaces, which have extended and promoted the use of modeling also to scientists not focusing on molecular structures of proteins. Nevertheless, construction of models of multi-protein complexes remains quite challenging for the non-experts, often due to the usage of specific procedures depending on the system under investigation and the need for experimental validation approaches to strengthen the generated output.In this chapter, we provide a brief overview of the approaches enabling generation of multi-protein complex models starting from homology models of individual protein components. Using real-life examples, we include two examples to guide the reader in the generation of homomeric and heteromeric protein models.
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Affiliation(s)
- Luigi Scietti
- Department of Biology and Biotechnology, The Armenise-Harvard Laboratory of Structural Biology, University of Pavia, Pavia, Italy.
| | - Federico Forneris
- Department of Biology and Biotechnology, The Armenise-Harvard Laboratory of Structural Biology, University of Pavia, Pavia, Italy.
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16
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Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders. Cells 2022; 11:cells11223702. [PMID: 36429129 PMCID: PMC9688865 DOI: 10.3390/cells11223702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/08/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022] Open
Abstract
Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
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17
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Penon-Portmann M, Westbury SK, Li L, Pluthero FG, Liu RJY, Yao HHY, Geng RSQ, Warner N, Muise AM, Lotz-Esquivel S, Howell-Ramirez M, Saborío-Chacon P, Fernández-Rojas S, Saborio-Rocafort M, Jiménez-Hernández M, Wang-Zuniga C, Cartín-Sánchez W, Shieh JT, Badilla-Porras R, Kahr WHA. Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome. J Thromb Haemost 2022; 20:1712-1719. [PMID: 35325493 DOI: 10.1111/jth.15711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Platelet α-granule biogenesis in precursor megakaryocytes is critically dependent on VPS33B and VPS16B, as demonstrated by the platelet α-granule deficiency seen in the rare multisystem disorder arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome associated with biallelic pathogenic variants in VPS33B and VIPAS39 (encoding VPS16B). VPS33B and VPS16B are ubiquitously expressed proteins that are known to interact and play key roles in protein sorting and trafficking between subcellular locations. However, there remain significant gaps in our knowledge of the nature of these interactions in primary cells from patients with ARC syndrome. OBJECTIVES To use primary cells from patients with ARC syndrome to better understand the interactions and roles of VPS33B and VPS16B in platelets and precursor megakaryocytes. PATIENTS/METHODS The proband and his male sibling were clinically suspected to have ARC syndrome. Confirmatory genetic testing and platelet phenotyping, including electron microscopy and protein expression analysis, was performed with consent in a research setting. RESULTS We describe the first case of ARC syndrome identified in Costa Rica, associated with a novel homozygous nonsense VPS33B variant that is linked with loss of expression of both VPS33B and VPS16B in platelets. CONCLUSION These results indicate that stable expression of VPS16B in platelets, their precursor megakaryocytes, and other cells is dependent on VPS33B. We suggest that systematic evaluation of primary cells from patients with a range of VPS33B and VIPAS39 variants would help to elucidate the interactions and functions of these proteins.
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Affiliation(s)
- Monica Penon-Portmann
- Servicio de Genética Médica y Metabolismo, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social (CCSS) & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
- Department of Pediatrics & Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
| | - Sarah K Westbury
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
- Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Ling Li
- Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Fred G Pluthero
- Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Richard J Y Liu
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Helen H Y Yao
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Ryan S Q Geng
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Neil Warner
- SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada
| | - Aleixo M Muise
- SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada
- Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada
| | - Stephanie Lotz-Esquivel
- Servicio de Genética Médica y Metabolismo, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social (CCSS) & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
- Clínica Multidisciplinaria de Enfermedades Raras y Huérfanas, Departamento de Medicina Interna, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, San José, Costa Rica
| | - Marianela Howell-Ramirez
- Servicio de Nefrología, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
| | - Pablo Saborío-Chacon
- Servicio de Nefrología, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
| | - Sara Fernández-Rojas
- Servicio de Nefrología, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
| | - Manuel Saborio-Rocafort
- Servicio de Genética Médica y Metabolismo, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social (CCSS) & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
- Programa Nacional de Tamizaje Neonatal, Caja Costarricense de Seguro Social, San José, Costa Rica
| | - Mildred Jiménez-Hernández
- Programa Nacional de Tamizaje Neonatal, Caja Costarricense de Seguro Social, San José, Costa Rica
- Laboratorio Nacional de Tamizaje Neonatal y Alto Riesgo, Caja Costarricense de Seguro Social, San José, Costa Rica
| | - Carolina Wang-Zuniga
- Servicio de Dermatología, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
| | - Walter Cartín-Sánchez
- Laboratorio de Estudios Especializados e Investigación, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social, San José, Costa Rica
| | - Joseph T Shieh
- Department of Pediatrics & Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
| | - Ramses Badilla-Porras
- Servicio de Genética Médica y Metabolismo, Departamento de Pediatría, Hospital Nacional de Niños, "Dr. Carlos Sáenz Herrera", Caja Costarricense de Seguro Social (CCSS) & Sistema de Estudios de Posgrado, Universidad de Costa Rica, San José, Costa Rica
- Laboratorio Nacional de Tamizaje Neonatal y Alto Riesgo, Caja Costarricense de Seguro Social, San José, Costa Rica
| | - Walter H A Kahr
- Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada
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18
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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19
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Bourguignon A, Tasneem S, Hayward CP. Screening and diagnosis of inherited platelet disorders. Crit Rev Clin Lab Sci 2022; 59:405-444. [PMID: 35341454 DOI: 10.1080/10408363.2022.2049199] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inherited platelet disorders are important conditions that often manifest with bleeding. These disorders have heterogeneous underlying pathologies. Some are syndromic disorders with non-blood phenotypic features, and others are associated with an increased predisposition to developing myelodysplasia and leukemia. Platelet disorders can present with thrombocytopenia, defects in platelet function, or both. As the underlying pathogenesis of inherited thrombocytopenias and platelet function disorders are quite diverse, their evaluation requires a thorough clinical assessment and specialized diagnostic tests, that often challenge diagnostic laboratories. At present, many of the commonly encountered, non-syndromic platelet disorders do not have a defined molecular cause. Nonetheless, significant progress has been made over the past few decades to improve the diagnostic evaluation of inherited platelet disorders, from the assessment of the bleeding history to improved standardization of light transmission aggregometry, which remains a "gold standard" test of platelet function. Some platelet disorder test findings are highly predictive of a bleeding disorder and some show association to symptoms of prolonged bleeding, surgical bleeding, and wound healing problems. Multiple assays can be required to diagnose common and rare platelet disorders, each requiring control of preanalytical, analytical, and post-analytical variables. The laboratory investigations of platelet disorders include evaluations of platelet counts, size, and morphology by light microscopy; assessments for aggregation defects; tests for dense granule deficiency; analyses of granule constituents and their release; platelet protein analysis by immunofluorescent staining or flow cytometry; tests of platelet procoagulant function; evaluations of platelet ultrastructure; high-throughput sequencing and other molecular diagnostic tests. The focus of this article is to review current methods for the diagnostic assessment of platelet function, with a focus on contemporary, best diagnostic laboratory practices, and relationships between clinical and laboratory findings.
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Affiliation(s)
- Alex Bourguignon
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Subia Tasneem
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Catherine P Hayward
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.,Department of Medicine, McMaster University, Hamilton, Canada
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20
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Satomura Y, Bessho K, Nawa N, Kondo H, Ito S, Togawa T, Yano M, Yamano Y, Inoue T, Fukui M, Onuma S, Fukuoka T, Yasuda K, Kimura T, Tachibana M, Kitaoka T, Nabatame S, Ozono K. Novel gene mutations in three Japanese patients with ARC syndrome associated mild phenotypes: a case series. J Med Case Rep 2022; 16:60. [PMID: 35151346 PMCID: PMC8841066 DOI: 10.1186/s13256-022-03279-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/18/2022] [Indexed: 11/17/2022] Open
Abstract
Background Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is a rare autosomal recessive disorder caused by mutations in VPS33B (ARCS1) and VIPAS39 (ARCS2). As per literature, most patients with ARCS died of persistent infections and bleeding by the age of 1 year. We report the first Japanese cases with ARCS1 and ARCS2 who presented with mild phenotypes and were diagnosed via genetic testing. Case presentation Case 1: A 6-year-old boy born to nonconsanguineous Japanese parents presented with jaundice and normal serum gamma-glutamyl transferase (GGT) levels, proteinuria, bilateral nerve deafness, motor delay, failure to thrive, and persistent pruritus. After cochlear implantation for deafness at the age of 2 years, despite a normal platelet count and prothrombin time-international normalized ratio, the patient presented with persistent bleeding that required hematoma removal. Although he did not show any obvious signs of arthrogryposis, he was suspected to have ARCS based on other symptoms. Compound heterozygous mutations in VPS33B were identified using targeted next-generation sequencing (NGS), which resulted in no protein expression. Case 2: A 7-month-old boy, the younger brother of case 1, presented with bilateral deafness, renal tubular dysfunction, failure to thrive, and mild cholestasis. He had the same mutations that were identified in his brother’s VPS33B. Case 3: A 24-year-old man born to nonconsanguineous Japanese parents was suspected to have progressive familial intrahepatic cholestasis 1 (PFIC1) in his childhood on the basis of low GGT cholestasis, renal tubular dysfunction, sensory deafness, mental retardation, and persistent itching. A liver biopsy performed at the age of 16 years showed findings that were consistent with PFIC1. He developed anemia owing to intraperitoneal hemorrhage from a peripheral intrahepatic artery the day after the biopsy, and transcatheter arterial embolization was required. ARCS2 was diagnosed using targeted NGS, which identified novel compound heterozygous mutations in VIPAS39. Conclusions The first Japanese cases of ARCS1 and ARCS2 diagnosed using genetic tests were reported in this study. These cases are milder than those previously reported. For patients with ARCS, invasive procedures should be performed with meticulous care to prevent bleeding.
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21
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Syntaxin 12 and COMMD3 are new factors that function with VPS33B in the biogenesis of platelet α-granules. Blood 2022; 139:922-935. [PMID: 34905616 PMCID: PMC8832482 DOI: 10.1182/blood.2021012056] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 11/30/2021] [Indexed: 11/20/2022] Open
Abstract
Platelet α-granules regulate hemostasis and myriad other physiological processes, but their biogenesis is unclear. Mutations in only 3 proteins are known to cause α-granule defects and bleeding disorders in humans. Two such proteins, VPS16B and VPS33B, form a complex mediating transport of newly synthesized α-granule proteins through megakaryocyte (MK) endosomal compartments. It is unclear how the VPS16B/VPS33B complex accomplishes this function. Here we report VPS16B/VPS33B associates physically with Syntaxin 12 (Stx12), a SNARE protein that mediates vesicle fusion at endosomes. Importantly, Stx12-deficient MKs display reduced α-granule numbers and overall levels of α-granule proteins, thus revealing Stx12 as a new component of the α-granule biogenesis machinery. VPS16B/VPS33B also binds CCDC22, a component of the CCC complex working at endosome exit sites. CCDC22 competes with Stx12 for binding to VPS16B/VPS33B, suggesting a possible hand-off mechanism. Moreover, the major CCC form expressed in MKs contains COMMD3, one of 10 COMMD proteins. Deficiency of COMMD3/CCDC22 causes reduced α-granule numbers and overall levels of α-granule proteins, establishing the COMMD3/CCC complex as a new factor in α-granule biogenesis. Furthermore, P-selectin traffics through the cell surface in a COMMD3-dependent manner and depletion of COMMD3 results in lysosomal degradation of P-selectin and PF4. Stx12 and COMMD3/CCC deficiency cause less severe phenotypes than VPS16B/VPS33B deficiency, suggesting Stx12 and COMMD3/CCC assist but are less important than VPS16B/VPS33B in α-granule biogenesis. Mechanistically, our results suggest VPS16B/VPS33B coordinates the endosomal entry and exit of α-granule proteins by linking the fusogenic machinery with a ubiquitous endosomal retrieval complex that is repurposed in MKs to make α-granules.
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22
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Thergaonkar R, Panale P, Jamal A, Bhat V. ARC syndrome: A rare cause of infantile cholestasis. JOURNAL OF MARINE MEDICAL SOCIETY 2022. [DOI: 10.4103/jmms.jmms_20_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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23
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Stalke A, Sgodda M, Cantz T, Skawran B, Lainka E, Hartleben B, Baumann U, Pfister ED. KIF12 Variants and Disturbed Hepatocyte Polarity in Children with a Phenotypic Spectrum of Cholestatic Liver Disease. J Pediatr 2022; 240:284-291.e9. [PMID: 34555379 DOI: 10.1016/j.jpeds.2021.09.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 01/03/2023]
Abstract
KIF12 has been identified as a cholestasis-associated candidate gene. We describe 6 cases from 4 unrelated families with diverse cholestatic phenotypes carrying 2 different homozygous KIF12 truncating variants. Immunofluorescence investigations of paraffin-embedded liver sections suggest that KIF12-associated impaired functional cell polarity may be the underlying cause.
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Affiliation(s)
- Amelie Stalke
- Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany; Department of Human Genetics, Hannover Medical School, Hannover, Germany.
| | - Malte Sgodda
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Britta Skawran
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Elke Lainka
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, University Children's Hospital Essen, Essen, Germany
| | - Björn Hartleben
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
| | - Eva-Doreen Pfister
- Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
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24
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Mahanty S, Setty SRG. Epidermal Lamellar Body Biogenesis: Insight Into the Roles of Golgi and Lysosomes. Front Cell Dev Biol 2021; 9:701950. [PMID: 34458262 PMCID: PMC8387949 DOI: 10.3389/fcell.2021.701950] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/09/2021] [Indexed: 12/25/2022] Open
Abstract
Epidermal lamellar bodies (eLBs) are secretory organelles that carry a wide variety of secretory cargo required for skin homeostasis. eLBs belong to the class of lysosome-related organelles (LROs), which are cell-type-specific organelles that perform diverse functions. The formation of eLBs is thought to be related to that of other LROs, which are formed either through the gradual maturation of Golgi/endosomal precursors or by the conversion of conventional lysosomes. Current evidence suggests that eLB biogenesis presumably initiate from trans-Golgi network and receive cargo from endosomes, and also acquire lysosome characteristics during maturation. These multistep biogenesis processes are frequently disrupted in human skin disorders. However, many gaps remain in our understanding of eLB biogenesis and their relationship to skin diseases. Here, we describe our current understanding on eLB biogenesis with a focus on cargo transport to this LRO and highlight key areas where future research is needed.
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Affiliation(s)
| | - Subba Rao Gangi Setty
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India
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25
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RAB10 Interacts with ABCB4 and Regulates Its Intracellular Traffic. Int J Mol Sci 2021; 22:ijms22137087. [PMID: 34209301 PMCID: PMC8268348 DOI: 10.3390/ijms22137087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022] Open
Abstract
ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for a significant proportion of patients with ABCB4-related diseases and liver transplantation is often required. The development of novel therapies requires a deep understanding of the molecular mechanisms regulating ABCB4 expression, intracellular traffic, and function. Using an immunoprecipitation approach combined with mass spectrometry analyses, we have identified the small GTPase RAB10 as a novel molecular partner of ABCB4. Our results indicate that the overexpression of wild type RAB10 or its dominant-active mutant significantly increases the amount of ABCB4 at the plasma membrane expression and its phosphatidylcholine floppase function. Contrariwise, RAB10 silencing induces the intracellular retention of ABCB4 and then indirectly diminishes its secretory function. Taken together, our findings suggest that RAB10 regulates the plasma membrane targeting of ABCB4 and consequently its capacity to mediate phosphatidylcholine secretion.
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26
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Yıldız Y, Koşukcu C, Aygün D, Akçaboy M, Öztek Çelebi FZ, Taşcı Yıldız Y, Şahin G, Aytekin C, Yüksel D, Lay İ, Özgül RK, Dursun A. Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings. Clin Genet 2021; 100:308-317. [PMID: 34013567 DOI: 10.1111/cge.14002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 12/17/2022]
Abstract
Disorders of intracellular trafficking are a group of inherited disorders, which often display multisystem phenotypes. Vacuolar protein sorting (VPS) subunit C, composed of VPS11, VPS18, VPS16, and VPS33A proteins, is involved in tethering of endosomes, lysosomes, and autophagosomes. Our group and others have previously described patients with a specific homozygous missense VPS33A variant, exhibiting a storage disease phenotype resembling mucopolysaccharidosis (MPS), termed "MPS-plus syndrome." Here, we report two siblings from a consanguineous Turkish-Arabic family, who have overlapping features of MPS and intracellular trafficking disorders, including short stature, coarse facies, developmental delay, peripheral neuropathy, splenomegaly, spondylar dysplasia, congenital neutropenia, and high-normal glycosaminoglycan excretion. Whole exome sequencing and familial segregation analyses led to the homozygous NM_022575.3:c.540G>T; p.Trp180Cys variant in VPS16 in both siblings. Multiple bioinformatic methods supported the pathogenicity of this variant. Different monoallelic null VPS16 variants and a homozygous missense VPS16 variant had been previously associated with dystonia. A biallelic intronic, probably splice-altering variant in VPS16, causing an MPS-plus syndrome-like disease has been very recently reported in two individuals. The siblings presented herein display no dystonia, but have features of a multisystem storage disorder, representing a novel MPS-plus syndrome-like disease, associated for the first time with VPS16 missense variants.
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Affiliation(s)
- Yılmaz Yıldız
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.,Department of Pediatric Metabolic Diseases, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Can Koşukcu
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.,Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Damla Aygün
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Meltem Akçaboy
- Department of Pediatrics, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Fatma Zehra Öztek Çelebi
- Department of Pediatrics, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Yasemin Taşcı Yıldız
- Department of Pediatric Radiology, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Gülseren Şahin
- Department of Pediatric Gastroenterology, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Caner Aytekin
- Department of Pediatric Allergy and Immunology, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - Deniz Yüksel
- Department of Pediatric Neurology, Dr. Sami Ulus Training and Research Hospital for Maternity and Child Health, Ankara, Turkey
| | - İncilay Lay
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Rıza Köksal Özgül
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.,Institute of Child Health, Hacettepe University, Ankara, Turkey
| | - Ali Dursun
- Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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27
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Schneeberger PE, Nampoothiri S, Holling T, Yesodharan D, Alawi M, Knisely AS, Müller T, Plecko B, Janecke AR, Kutsche K. Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis. Brain 2021; 144:3036-3049. [PMID: 34037727 DOI: 10.1093/brain/awab206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 11/14/2022] Open
Abstract
Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52, and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the TGN is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient neonatal cholestasis, and failure to thrive. Light and transmission electron microscopy of liver from one revealed absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes, and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While transferrin-receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy, and variable atrophy of the cerebellum, cerebrum, and/or brainstem. The term "GARP/EARP deficiency" designates disorders in such individuals.
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Affiliation(s)
- Pauline E Schneeberger
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Sheela Nampoothiri
- Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin 682041, Kerala, India
| | - Tess Holling
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Dhanya Yesodharan
- Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin 682041, Kerala, India
| | - Malik Alawi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - A S Knisely
- Institut für Pathologie, Medizinische Universität Graz, 8010 Graz, Austria
| | - Thomas Müller
- Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Barbara Plecko
- Department of Pediatrics, Division of General Pediatrics, Medical University of Graz, 8010 Graz, Austria
| | - Andreas R Janecke
- Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.,Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Kerstin Kutsche
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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28
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Bull LN, Ellmers R, Foskett P, Strautnieks S, Sambrotta M, Czubkowski P, Jankowska I, Wagner B, Deheragoda M, Thompson RJ. Cholestasis Due to USP53 Deficiency. J Pediatr Gastroenterol Nutr 2021; 72:667-673. [PMID: 33075013 PMCID: PMC8549450 DOI: 10.1097/mpg.0000000000002926] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients. METHODS Whole exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next-generation sequencing (NGS). Disease features at presentation and follow-up were collected from available medical records. RESULTS By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53 in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound. CONCLUSIONS Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53 in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long-term follow-up is recommended.
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Affiliation(s)
- Laura N. Bull
- Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California San Francisco, San Francisco, CA
| | | | | | | | | | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Bart Wagner
- Histopathology Department, Royal Hallamshire Hospital, Sheffield, UK
| | | | - Richard J. Thompson
- Institute of Liver Studies, King's College Hospital
- Institute of Liver Studies, King's College London, London, UK
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29
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A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators. BIOLOGY 2021; 10:biology10020119. [PMID: 33557414 PMCID: PMC7914782 DOI: 10.3390/biology10020119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary Cholestasis refers to a medical condition in which the liver is not capable of secreting bile. The consequent accumulation of toxic bile components in the liver leads to liver failure. Cholestasis can be caused by mutations in genes that code for proteins involved in bile secretion. Recently mutations in other genes have been discovered in patients with cholestasis of unknown origin. Interestingly, many of these newly discovered genes code for proteins that regulate the intracellular distribution of other proteins, including those involved in bile secretion. This group of genes thus suggests the deregulated intracellular distribution of bile-secreting proteins as an important but still poorly understood mechanism that underlies cholestasis. To expedite a better understanding of this mechanism, we have reviewed these genes and their mutations and we discuss these in the context of cholestasis. Abstract Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1H4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.
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30
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Pluthero FG, Kahr WHA. Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects. J Thromb Haemost 2021; 19:318-322. [PMID: 33300270 DOI: 10.1111/jth.15177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 11/06/2020] [Indexed: 01/13/2023]
Affiliation(s)
- Fred G Pluthero
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
| | - Walter H A Kahr
- Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
- Division of Haematology/Oncology, Department of Paediatrics, University of Toronto and the Hospital for Sick Children, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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31
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Lemaire M. Novel Fanconi renotubular syndromes provide insights in proximal tubule pathophysiology. Am J Physiol Renal Physiol 2020; 320:F145-F160. [PMID: 33283647 DOI: 10.1152/ajprenal.00214.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase (GATM), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 (SLC34A1), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), hepatocyte nuclear factor 4A (HNF4A), or NADH dehydrogenase complex I, assembly factor 6 (NDUFAF6). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 (SLC34A1). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.
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Affiliation(s)
- Mathieu Lemaire
- Division of Nephrology and Cell Biology Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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32
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Evans HM, Siew SM. Neonatal liver disease. J Paediatr Child Health 2020; 56:1760-1768. [PMID: 33197975 DOI: 10.1111/jpc.15064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 06/22/2020] [Accepted: 06/22/2020] [Indexed: 12/01/2022]
Abstract
Neonatal liver disease encompasses many diagnoses, including structural and genetic aetiologies. Many have significant health implications requiring long-term specialist treatment including liver transplantation. Jaundice is a common presenting feature. The ability of health-care professionals to differentiate neonatal liver disease from benign diagnoses such as physiological jaundice is very important. Persistent (more than 2 weeks) of conjugated jaundice always warrants investigation. Severe unconjugated jaundice (requiring prolonged phototherapy) should also be promptly investigated. Recent advances in genomics have enabled previously elusive, precise diagnoses in some patients with neonatal liver disease. This review paper discusses the commoner causes, with a focus on early detection and need for referral to paediatric liver services.
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Affiliation(s)
- Helen M Evans
- Department of Paediatric Gastroenterology and Hepatology, Starship Child Health, Auckland, New Zealand.,Department of Paediatrics, University of Auckland, Auckland, New Zealand
| | - Susan M Siew
- Department of Gastroenterology and James Fairfax Institute of Paediatric Nutrition, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
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33
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A Novel Mutation of VPS33 B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype. Case Rep Genet 2020; 2020:8872294. [PMID: 33029437 PMCID: PMC7532373 DOI: 10.1155/2020/8872294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/28/2020] [Accepted: 09/12/2020] [Indexed: 02/05/2023] Open
Abstract
Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations of the VPS33B encoding the vacuolar protein sorting 33B (VPS33B), which is involved in the intracellular protein sorting and vesicular trafficking. We report a rare case of ARC syndrome without arthrogryposis caused by a novel mutation of VPS33B. A female patient of Greek origin presented on the 14th day of life with renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and cholestasis with normal gamma-glutamyl transpeptidase, without arthrogryposis and dysmorphic features. She was born to apparently healthy, nonconsanguineous parents. Additional features included dry and scaling skin, generalized hypotonia, hypoplastic corpus callosum, neurodevelopmental delay, failure to thrive, short stature, recurrent febrile episodes with and without infections, and gastrointestinal bleeding. DNA testing revealed that the patient was homozygous for the novel c.1098_1099delTG (p.Glu367Alafs∗17) mutation of exon 14 of VPS33B gene (NM_018668) on chromosome 15q26.1, leading to a nonsense frameshift variant of VPS33B with premature termination of translation. Her parents were heterozygous for the same VPS33B mutation. The prognosis was predictably poor in the context of the intractable polyuria necessitating long-term parenteral fluid administration via indwelling central catheter leading to catheter-related sepsis, to which she eventually succumbed at the age of 7 months. This is the first published VPS33B mutation in an ARC patient of Greek origin. The current case adds to the spectrum of ARC-associated VPS33B mutations and provides evidence supporting the existence of incomplete ARC phenotype. Increased awareness and early genetic testing for ARC are suggested in cases with isolated cholestasis and/or renal tubular dysfunction, even in the absence of arthrogryposis.
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Al-Huniti A, Kahr WH. Inherited Platelet Disorders: Diagnosis and Management. Transfus Med Rev 2020; 34:277-285. [PMID: 33082057 DOI: 10.1016/j.tmrv.2020.09.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/22/2022]
Abstract
Inherited platelet disorders are rare but they can have considerable clinical impacts, and studies of their causes have advanced understanding of platelet formation and function. Effective hemostasis requires adequate circulating numbers of functional platelets. Quantitative, qualitative and combined platelet disorders with a bleeding phenotype have been linked to defects in platelet cytoskeletal elements, cell surface receptors, signal transduction pathways, secretory granules and other aspects. Inherited platelet disorders have variable clinical presentations, and diagnosis and management is often challenging. Evaluation begins with detailed patient and family histories, including a bleeding score. The physical exam identifies potential syndromic features of inherited platelet disorders and rules out other causes. Laboratory investigations include a complete blood count, blood film, coagulation testing and Von Willebrand factor assessment. A suspected platelet function disorder is further assessed by platelet aggregation, flow cytometry, platelet dense granule release and/or content, and genetic testing. The management of platelet function disorders aims to minimize the risk of bleeding and achieve adequate hemostasis when needed. Although not universal, platelet transfusion remains a crucial component in the management of many inherited platelet disorders.
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Affiliation(s)
- Ahmad Al-Huniti
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
| | - Walter Ha Kahr
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada; Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada; Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, ON, Canada.
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Mechanism of platelet α-granule biogenesis: study of cargo transport and the VPS33B-VPS16B complex in a model system. Blood Adv 2020; 3:2617-2626. [PMID: 31501156 DOI: 10.1182/bloodadvances.2018028969] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 07/30/2019] [Indexed: 12/29/2022] Open
Abstract
Platelet α-granules play important roles in platelet function. They contain hundreds of proteins that are synthesized by the megakaryocyte or taken up by endocytosis. The trafficking pathways that mediate platelet α-granule biogenesis are incompletely understood, especially with regard to cargo synthesized by the megakaryocyte. Vacuolar-protein sorting 33B (VPS33B) and VPS16B are essential proteins for α-granule biogenesis, but they are largely uncharacterized. Here, we adapted a powerful method to directly map the pathway followed by newly synthesized cargo proteins to reach α-granules. Using this method, we revealed the recycling endosome as a key intermediate compartment in α-granule biogenesis. We then used CRISPR/Cas9 gene editing to knock out VPS33B in pluripotent stem cell-derived immortalized megakaryocyte cells (imMKCLs). Consistent with the observations in platelets from patients with VPS33B mutation, VPS33B-knockout (KO) imMKCLs have drastically reduced levels of α-granule proteins platelet factor 4, von Willebrand factor, and P-selectin. VPS33B and VPS16B form a distinct and small complex in imMKCLs with the same hydrodynamic radius as the recombinant VPS33B-VPS16B heterodimer purified from bacteria. Mechanistically, the VPS33B-VPS16B complex ensures the correct trafficking of α-granule proteins. VPS33B deficiency results in α-granule cargo degradation in lysosomes. VPS16B steady-state levels are significantly lower in VPS33B-KO imMKCLs, suggesting that VPS16B is destabilized in the absence of its partner. Exogenous expression of green fluorescent protein-VPS33B in VPS33B-KO imMKCLs reconstitutes the complex, which localizes to the recycling endosome, further defining this compartment as a key intermediate in α-granule biogenesis. These results advance our understanding of platelet α-granule biogenesis and open new avenues for the study of these organelles.
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Zhang J, Tracy C, Pasare C, Zeng J, Krämer H. Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase. Traffic 2020; 21:578-589. [PMID: 32677257 DOI: 10.1111/tra.12756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 07/10/2020] [Accepted: 07/12/2020] [Indexed: 11/29/2022]
Abstract
Loss of the arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome-linked Vps33B protein results in exaggerated inflammatory responses upon activation of receptors of the innate immune system in both vertebrates and flies. However, little is known about the signaling elements downstream of these receptors that are critical for the hypersensitivity of Vps33B mutants. Here, we show that p38b MAP kinase contributes to the enhanced inflammatory responses in flies lacking Vps33B. Loss of p38b mitogen-activated protein kinase (MAPK) reduces enhanced inflammatory responses and prolongs the survival of infected Vps33B deficient flies. The function of p38 MAPK is not limited to its proinflammatory effects downstream of the PGRP-LC receptor as p38 also modulates endosomal trafficking of PGRP-LC and phagocytosis of bacteria. Expression of constitutively active p38b MAPK, but not dominant negative p38b MAPK enhances accumulation of endocytosed PGRP-LC receptors or phagocytosed bacteria within cells. Moreover, p38 MAPK is required for induction of macropinocytosis, an alternate pathway for the downregulation of immune receptors. Together, our data indicate that p38 MAPK activates multiple pathways that can contribute to the dysregulation of innate immune signaling in ARC syndrome.
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Affiliation(s)
- Jian Zhang
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas, USA.,Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Charles Tracy
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Chandrashekhar Pasare
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
| | - Jinsheng Zeng
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
| | - Helmut Krämer
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas, USA.,Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA
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Bowman SL, Bi-Karchin J, Le L, Marks MS. The road to lysosome-related organelles: Insights from Hermansky-Pudlak syndrome and other rare diseases. Traffic 2020; 20:404-435. [PMID: 30945407 DOI: 10.1111/tra.12646] [Citation(s) in RCA: 149] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 12/11/2022]
Abstract
Lysosome-related organelles (LROs) comprise a diverse group of cell type-specific, membrane-bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky-Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion.
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Affiliation(s)
- Shanna L Bowman
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jing Bi-Karchin
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Linh Le
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael S Marks
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Karampini E, Bierings R, Voorberg J. Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles. Arterioscler Thromb Vasc Biol 2020; 40:1441-1453. [PMID: 32375545 DOI: 10.1161/atvbaha.120.314245] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.
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Affiliation(s)
- Ellie Karampini
- From the Department of Molecular and Cellular Hemostasis, Sanquin Research and Landsteiner Laboratory (E.K., R.B., J.V.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
| | - Ruben Bierings
- From the Department of Molecular and Cellular Hemostasis, Sanquin Research and Landsteiner Laboratory (E.K., R.B., J.V.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands.,Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands (R.B.)
| | - Jan Voorberg
- From the Department of Molecular and Cellular Hemostasis, Sanquin Research and Landsteiner Laboratory (E.K., R.B., J.V.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands.,Experimental Vascular Medicine (J.V.), Amsterdam University Medical Center, University of Amsterdam, the Netherlands
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Yarwood R, Hellicar J, Woodman PG, Lowe M. Membrane trafficking in health and disease. Dis Model Mech 2020; 13:13/4/dmm043448. [PMID: 32433026 PMCID: PMC7197876 DOI: 10.1242/dmm.043448] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Membrane trafficking pathways are essential for the viability and growth of cells, and play a major role in the interaction of cells with their environment. In this At a Glance article and accompanying poster, we outline the major cellular trafficking pathways and discuss how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans. We also briefly discuss possible therapeutic approaches that may be used in the future treatment of trafficking-based disorders. Summary: This At a Glance article and poster summarise the major intracellular membrane trafficking pathways and associated molecular machineries, and describe how defects in these give rise to disease in humans.
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Affiliation(s)
- Rebecca Yarwood
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - John Hellicar
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Philip G Woodman
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Martin Lowe
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
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40
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Sparvoli D, Zoltner M, Cheng CY, Field MC, Turkewitz AP. Diversification of CORVET tethers facilitates transport complexity in Tetrahymena thermophila. J Cell Sci 2020; 133:jcs238659. [PMID: 31964712 PMCID: PMC7033735 DOI: 10.1242/jcs.238659] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 01/03/2020] [Indexed: 12/14/2022] Open
Abstract
In endolysosomal networks, two hetero-hexameric tethers called HOPS and CORVET are found widely throughout eukaryotes. The unicellular ciliate Tetrahymena thermophila possesses elaborate endolysosomal structures, but curiously both it and related protozoa lack the HOPS tether and several other trafficking proteins, while retaining the related CORVET complex. Here, we show that Tetrahymena encodes multiple paralogs of most CORVET subunits, which assemble into six distinct complexes. Each complex has a unique subunit composition and, significantly, shows unique localization, indicating participation in distinct pathways. One pair of complexes differ by a single subunit (Vps8), but have late endosomal versus recycling endosome locations. While Vps8 subunits are thus prime determinants for targeting and functional specificity, determinants exist on all subunits except Vps11. This unprecedented expansion and diversification of CORVET provides a potent example of tether flexibility, and illustrates how 'backfilling' following secondary losses of trafficking genes can provide a mechanism for evolution of new pathways.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Daniela Sparvoli
- Department of Molecular Genetics and Cell Biology, 920 E 58th Street, The University of Chicago, Chicago, IL, 60637, USA
| | - Martin Zoltner
- School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Chao-Yin Cheng
- Department of Molecular Genetics and Cell Biology, 920 E 58th Street, The University of Chicago, Chicago, IL, 60637, USA
| | - Mark C Field
- School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
- Biology Centre, Institute of Parasitology, Czech Academy of Sciences, 37005 Ceske Budejovice, Czech Republic
| | - Aaron P Turkewitz
- Department of Molecular Genetics and Cell Biology, 920 E 58th Street, The University of Chicago, Chicago, IL, 60637, USA
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41
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Lee MJ, Suh CR, Shin JH, Lee JH, Lee Y, Eun BL, Yoo KH, Shim JO. A Novel VPS33B Variant Identified by Exome Sequencing in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome. Pediatr Gastroenterol Hepatol Nutr 2019; 22:581-587. [PMID: 31777725 PMCID: PMC6856508 DOI: 10.5223/pghn.2019.22.6.581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/31/2019] [Indexed: 11/15/2022] Open
Abstract
Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystemic disease that is associated with the liver, kidney, skin, and central nervous and musculoskeletal systems. ARC occurs as a result of mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) or VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes. A female infant presented with neonatal cholestasis with a severe clinical outcome. She was diagnosed with ARC syndrome using targeted exome sequencing (TES). Exome sequencing revealed compound heterozygous mutations, c.707A>T and c.239+5G>A, in VPS33B, where c.707A>T was a novel variant; the resultant functional protein defects were predicted via in silico analysis. c.239+5G>A, a pathogenic mutation that affects splicing, is found in less than 0.1% of the general population. Invasive techniques, such as liver biopsies, did not contribute to a differential diagnosis of ARC syndrome; thus, early TES together with clinical presentations constituted an apparently accurate diagnostic procedure.
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Affiliation(s)
- Min Ju Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Chae Ri Suh
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jeong Hee Shin
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jee Hyun Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Yoon Lee
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Baik-Lin Eun
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Kee Hwan Yoo
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Jung Ok Shim
- Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
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42
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Qiu YL, Liu T, Abuduxikuer K, Hao CZ, Gong JY, Zhang MH, Li LT, Yan YY, Li JQ, Wang JS. Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome. Hum Mutat 2019; 40:2247-2257. [PMID: 31479177 DOI: 10.1002/humu.23770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 04/11/2019] [Accepted: 04/18/2019] [Indexed: 01/04/2023]
Abstract
The typical phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome involves three cardinal symptoms as the name describes, harboring biallelic mutations on VPS33B or VIPAS39. Except for ARC syndrome, low gamma-glutamyltransferase (GGT) cholestasis often implies hereditary hepatopathy of different severity; however, some remain undiagnosed. Several monogenic defects typically with multiorgan manifestations may only present liver dysfunction at times, such as DGUOK defect and AGL defect. Previously, four VPS33B mutated cases were reported without arthrogryposis, or with less severe symptoms and longer lifespan, indicating the possibility of incomplete ARC phenotype of isolated hepatopathy. So we retrospectively reviewed all patients with confirmed VPS33B/VIPARS39 defect in our center and identified three presenting isolated low-GGT cholestasis with intractable pruritus. Distinguished from others with typical ARC phenotype, these patients did not suffer the other two typical characteristics, survived much longer, and shared a novel missense VPS33B variation c.1726T>C, p.Cys576Arg, causing declined protein expression and abolished interaction with VIPAS39 in-vitro. Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.
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Affiliation(s)
- Yi-Ling Qiu
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Teng Liu
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | | | - Chen-Zhi Hao
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jing-Yu Gong
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Mei-Hong Zhang
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Li-Ting Li
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Yan-Yan Yan
- The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jia-Qi Li
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jian-She Wang
- The Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.,The Center for Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
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43
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Lemaigre FP. Development of the Intrahepatic and Extrahepatic Biliary Tract: A Framework for Understanding Congenital Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 15:1-22. [PMID: 31299162 DOI: 10.1146/annurev-pathmechdis-012418-013013] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.
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Affiliation(s)
- Frédéric P Lemaigre
- de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;
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44
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Ferreira CR, Cassiman D, Blau N. Clinical and biochemical footprints of inherited metabolic diseases. II. Metabolic liver diseases. Mol Genet Metab 2019; 127:117-121. [PMID: 31005404 PMCID: PMC10515611 DOI: 10.1016/j.ymgme.2019.04.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 12/14/2022]
Abstract
Inherited metabolic diseases account for about one third of pediatric patients with hepatomegaly, acute liver failure, cirrhosis or cholestasis. Specifically for pediatric acute liver failure, they account for 10-15% of cases, with a mortality of 22-65%. The percentage of acute liver failure caused by an inherited metabolic disease in children <2-3 years of age is even higher, ranging from a third to half of all cases. Metabolic liver disease accounts for 8-13% of all pediatric liver transplantations. Despite this high burden of disease, underdiagnosis remains common. We reviewed and updated the list of known metabolic etiologies associated with various types of metabolic liver involvement, and found 142 relevant inborn errors of metabolism. This represents the second of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.
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Affiliation(s)
- Carlos R Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
| | - David Cassiman
- Department of Gastroenterology-Hepatology and Metabolic Center, University of Leuven, Leuven, Belgium.
| | - Nenad Blau
- Dietmar-Hopp Metabolic Center, University Children's Hospital, Heidelberg, Germany; Division of Metabolism, Children's Hospital, Zürich, Switzerland.
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45
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Gillingham AK, Munro S. Transport carrier tethering - how vesicles are captured by organelles. Curr Opin Cell Biol 2019; 59:140-146. [PMID: 31154044 DOI: 10.1016/j.ceb.2019.04.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 12/20/2022]
Abstract
All cells contain numerous membrane-bound organelles that carry out specific functions. These compartments do not, however, act in isolation. Some are in direct contact via membrane contact sites, while others exchange material via specific vesicles or tubular carriers laden with cargo. The term tethering in the context of this review is used to describe the primary recognition and docking of transport carriers with acceptor organelles that occurs before SNARE engagement and membrane fusion. However, it is important to note that other tethering events occur, for example, between organelles in direct contact, which do not lead to fusion.
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Affiliation(s)
- Alison K Gillingham
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
| | - Sean Munro
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
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46
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[Syndromes with scales and keratosis]. Hautarzt 2019; 70:497-505. [PMID: 31087125 DOI: 10.1007/s00105-019-4417-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Approximately 9000 different phenotypes are known in medicine. The definition phenotype includes both manifest diseases as well as features without any disease value and the pure genetic disposition to develop a disease (e.g. tumors or complex diseases); however, most phenotypes are rare monogenic hereditary diseases. Approximately 6400 of these phenotypes have so far been elucidated by molecular genetics and are caused by mutations in 4064 different genes. Of all genetic diseases, an estimated one third are associated with skin symptoms. Genodermatoses are the phenotypes predominantly related to the skin, of which approximately 600 are familiar to dermatologists. The syndromes with scaling and keratosis include cornification disorders where the symptoms are not limited to the skin. They are associated with skin symptoms such as ichthyosis, erythroderma and palmoplantar keratoderma but show additional symptoms from other organ groups. The typical combination of symptoms may be unique to a syndrome and therefore seminal for the diagnosis.
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van der Beek J, Jonker C, van der Welle R, Liv N, Klumperman J. CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease. J Cell Sci 2019; 132:132/10/jcs189134. [DOI: 10.1242/jcs.189134] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
ABSTRACT
Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.
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Affiliation(s)
- Jan van der Beek
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Caspar Jonker
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Reini van der Welle
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Nalan Liv
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
| | - Judith Klumperman
- Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Institute for Biomembranes, Utrecht University, Utrecht 3584 CX, The Netherlands
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del Brío Castillo R, Squires JE, McKiernan PJ. A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival. JIMD Rep 2019; 47:4-8. [PMID: 31240160 PMCID: PMC6498830 DOI: 10.1002/jmd2.12027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 02/15/2019] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is an uncommon multisystem disorder that entails a very poor prognosis. It is caused by mutations in either VPS33B or VIPAS39 gene, both playing a key role in intracellular trafficking. We report two siblings born to first cousin parents with a novel mutation in VPS33B who have both shown prolonged survival. CASES PRESENTATION The index patient presented with bilateral hip dysplasia and arthrogryposis, failure to thrive, undernourishment, developmental delay, and low gamma-glutamyl transferase cholestasis. She at age 2 years underwent external biliary diversion with improvement in pruritus but liver disease continued to progress. She developed stomal bleeding at 7 years of age and liver biopsy displayed cirrhosis. Her 3-year-old sibling showed a similar trajectory as well as he had ichthyotic skin with excoriations. Their renal involvement was mild and stable. Genetic analysis in both patients revealed a novel homozygous mutation in NM_018668.4 (VPS33B):c.1157A > C (p.His386Pro). CONCLUSIONS ARC syndrome is a severe disorder with few patients reported to survive beyond 12 months of age. This report discloses a novel mutation in the VPS33B gene and describes a phenotype with prolonged survival, mild renal involvement, and progressive liver disease.
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Affiliation(s)
| | - James E. Squires
- Pediatric HepatologyChildren's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical CenterPittsburghPennsylvania
| | - Patrick J. McKiernan
- Pediatric HepatologyChildren's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical CenterPittsburghPennsylvania
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Fotoulaki M, Giza S, Jirsa M, Grammatikopoulos T, Miquel R, Hytiroglou P, Tsitouridis I, Knisely AS. Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations. Pediatrics 2019; 143:peds.2018-2146. [PMID: 31015375 DOI: 10.1542/peds.2018-2146] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2018] [Indexed: 11/24/2022] Open
Abstract
A 27-month-old girl presented with a short history of jaundice initially attributed to drug-induced liver injury. During the preceding 20 days, she had received a 10-day course of cefprozil and 2 doses of a homeopathic preparation of cantharidin for cystitis. Severe conjugated hyperbilirubinemia was present with normal γ-glutamyl transpeptidase activity. Liver biopsy revealed marked canalicular and hepatocellular cholestasis, with moderate hepatocellular disarray, as well as evidence of chronicity, including moderate portal-tract and perisinusoidal fibrosis. Immunohistochemical studies revealed that bile salt export pump expression was preserved, whereas canalicular γ-glutamyl transpeptidase expression was largely absent. An inherited cholestatic disorder was suspected. The entire coding region of ABCB11, encoding bile salt export pump, was analyzed. The patient was found to be a compound heterozygote for the missense mutation c.3148C>T (p.Arg1050Cys) associated with benign recurrent intrahepatic cholestasis type 2 in the homozygous state and for the nonsense mutation c.3904G>T (p.Glu1302Ter) associated with progressive familial intrahepatic cholestasis type 2. Despite initial improvement with ursodeoxycholic acid, over the course of 5 years the patient developed cirrhosis that required liver transplant. Our report emphasizes the need for molecular studies even in patients with putatively "explained" cholestasis to reveal the entire spectrum of inherited cholestatic disorders.
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Affiliation(s)
| | | | - Milan Jirsa
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | | | - Rosa Miquel
- Liver Histopathology Service, Institute of Liver Studies, King's College Hospital, London, United Kingdom; and
| | - Prodromos Hytiroglou
- Department of Pathology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki and
| | - Ioannis Tsitouridis
- Department of Radiology, Papageorgiou General Hospital of Thessaloniki, Thessaloniki, Greece
| | - A S Knisely
- Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
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Fu K, Wang C, Gao Y, Fan S, Zhang H, Sun J, Jiang Y, Liu C, Guan L, Liu J, Huang M, Bi H. Metabolomics and Lipidomics Reveal the Effect of Hepatic Vps33b Deficiency on Bile Acids and Lipids Metabolism. Front Pharmacol 2019; 10:276. [PMID: 30967781 PMCID: PMC6439481 DOI: 10.3389/fphar.2019.00276] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/04/2019] [Indexed: 12/16/2022] Open
Abstract
Vascular protein sorting-associated protein 33B (VPS33B) plays important roles in hepatic polarity, which directly maintains the functional structure of the liver. It has reported that VPS33B has close association with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome. Unfortunately, no further studies were conducted to reveal the role of Vps33b in the homeostasis of bile acids. In the current study, hepatic Vps33b-depleted male mice were used to investigate the metabolomics and lipidomics profiles of hepatic Vps33b deficiency based on ultrahigh-performance liquid chromatography coupled with an electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) system. Hepatic Vps33b-depleted male mice displayed cholestasis and slight liver damage with increased serum levels of ALT, AST, ALP and T-Bili compared to wild-type mice. Targeted metabolomics analysis of bile acids revealed that increased taurine-conjugated bile acids accumulated in the serum of hepatic Vps33b-depleted mice, while unconjugated bile acids were prone to decrease, accompanied by the regulation of bile acid homeostasis-related genes. In addition, lipid profiles were significantly altered with the lack of Vps33b in the liver. A variety of lipids, such as triglycerides and sphingomyelins, were significantly decreased in the liver and increased in the serum of hepatic Vps33b-depleted mice compared to those in wild-type mice. Our study demonstrated that Vps33b influences the progress of liver metabolism both in bile acid circulation and lipid metabolism, which is involved in the progression of liver cholestasis in mice.
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Affiliation(s)
- Kaili Fu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Conghui Wang
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Gao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shicheng Fan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huizhen Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiahong Sun
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yiming Jiang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Conghui Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lihuan Guan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Junling Liu
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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