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Socha P, Jańczyk W, Zanetto A, Burra P, Czlonkowska A, Debray D, Ferenci P, Merle U, Nicastro E, Poujois A, Schmidt H, Tsochatzis E. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol 2025; 82:S0168-8278(24)02706-5. [PMID: 40089450 DOI: 10.1016/j.jhep.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 03/17/2025]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism which affects the liver, brain and other organs. Diagnosis is based on: clinical features; biochemical tests, including plasma ceruloplasmin concentration, 24-h urinary copper excretion, copper content in the liver; and molecular analysis. Leipzig score and additionally relative exchangeable copper determination are recommended for diagnosis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts, while only chelators are recommended for significant liver disease. Monitoring is based on clinical symptoms, liver tests and copper metabolism (urinary copper excretion, exchangeable copper) to detect poor compliance and over/under-treatment. Acute liver failure is challenging as making a diagnosis is difficult and pharmacological therapy may not be sufficient to save life. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure but may also be considered in neurological disease.
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Rackova M, Mattera R, Svaton M, Fencl F, Kanderova V, Spicakova K, Park SY, Fabian O, Koblizek M, Fronkova E, Bonifacino JS, Skvarova Kramarzova K. Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion. J Mol Med (Berl) 2024; 102:1343-1353. [PMID: 39269494 PMCID: PMC11525306 DOI: 10.1007/s00109-024-02482-0] [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: 05/06/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024]
Abstract
MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.
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Affiliation(s)
- Marketa Rackova
- CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Rafael Mattera
- Section on Intracellular Protein Trafficking, Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Michael Svaton
- CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Filip Fencl
- Department of Pediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Veronika Kanderova
- CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Karolina Spicakova
- Department of Pediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Sang Yoon Park
- Section on Intracellular Protein Trafficking, Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Ondrej Fabian
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Miroslav Koblizek
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Eva Fronkova
- CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Juan S Bonifacino
- Section on Intracellular Protein Trafficking, Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
| | - Karolina Skvarova Kramarzova
- CLIP, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
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Pham VVH, Jue TR, Bell JL, Luciani F, Michniewicz F, Cirillo G, Vahdat L, Mayoh C, Vittorio O. A novel network-based method identifies a cuproplasia-related pan-cancer gene signature to predict patient outcome. Hum Genet 2024; 143:1145-1162. [PMID: 38642129 PMCID: PMC11485146 DOI: 10.1007/s00439-024-02673-2] [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: 10/11/2023] [Accepted: 03/26/2024] [Indexed: 04/22/2024]
Abstract
Copper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. Utilising RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, we generated gene regulatory networks to identify the critical cuproplasia-related genes across 23 different cancer types. From this, we identified a novel 8-gene cuproplasia-related gene signature associated with pan-cancer survival, and a 6-gene prognostic risk score model in low grade glioma. These findings highlight the use of gene regulatory networks to identify cuproplasia-related gene signatures that could be used to generate risk score models. This can potentially identify patients who could benefit from copper-chelation therapy and identifies novel targeted therapeutic strategies.
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Affiliation(s)
- Vu Viet Hoang Pham
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia
| | - Toni Rose Jue
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia
| | - Jessica Lilian Bell
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia
| | - Fabio Luciani
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia
| | - Filip Michniewicz
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia
| | - Giuseppe Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Linda Vahdat
- Dartmouth-Hitchcock Medical Center: Lebanon, New Hampshire, US
| | - Chelsea Mayoh
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia
| | - Orazio Vittorio
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Kensington, NSW, Australia.
- School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia.
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Hao D, Luo W, Yan Y, Zhou J. Focus on cuproptosis: Exploring new mechanisms and therapeutic application prospects of cuproptosis regulation. Biomed Pharmacother 2024; 178:117182. [PMID: 39053428 DOI: 10.1016/j.biopha.2024.117182] [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: 05/26/2024] [Revised: 07/15/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024] Open
Abstract
Cuproptosis is a novel form of regulated cell death, which plays an important role in the physiological and pathological processes of the human body. Despite the increasing research on cuproptosis-related genes (CRGs) and their correlation with diseases, the pathogenesis of cuproptosis-related diseases remains unclear. Furthermore, there is a lack of reviews on the emerging technologies for regulating cuproptosis in disease treatment. This study delves into the copper-induced cell death mechanism, distinguishing cuproptosis from mechanisms like oxidative stress, glutathione synthesis inhibition, and ubiquitin-proteasome system inhibition. Several long-standing mysteries of diseases such as Wilson's disease and Menkes disease may be attributed to the occurrence of cuproptosis. In addition, we also review the detection indicators related to cuproptosis, providing targets for the diagnosis of cuproptosis-related diseases, and summarize the application value of cuproptosis in tumor therapy to better elucidate the impact of copper in cell death and diseases, and thus to promote the application prospects and possible strategies of cuproptosis-related substances, such as copper ion chelators, copper ion carriers, and copper nanomaterials, in disease therapy.
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Affiliation(s)
- Donglin Hao
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China; Changzhou Medical Center, Nanjing Medical University, Changzhou, China
| | - Wei Luo
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China; Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Yongmin Yan
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China; Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China.
| | - Jing Zhou
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China; Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China.
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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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Lafhal K, Fdil N. Wilson Disease: Diagnostic Challenges and Differential Diagnoses. CLINICAL & TRANSLATIONAL METABOLISM 2024; 22:6. [DOI: 10.1007/s12018-024-09294-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/16/2024] [Indexed: 01/05/2025]
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Yang Z, Feng R, Zhao H. Cuproptosis and Cu: a new paradigm in cellular death and their role in non-cancerous diseases. Apoptosis 2024:10.1007/s10495-024-01993-y. [PMID: 39014119 DOI: 10.1007/s10495-024-01993-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2024] [Indexed: 07/18/2024]
Abstract
Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson's disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation.
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Affiliation(s)
- Zhibo Yang
- Department of Neurosurgery, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, 723000, Shaanxi, China
| | - Ridong Feng
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU), 79 Qingchun Rd., Shangcheng District, Hangzhou, 330100, Zhejiang, China
| | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, 266005, Shandong, China.
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Zhu J, Liao Y, Li X, Jia F, Ma X, Qu H. Brain and the whole-body bone imaging appearances in Menkes disease: a case report and literature review. BMC Pediatr 2024; 24:411. [PMID: 38926644 PMCID: PMC11202368 DOI: 10.1186/s12887-024-04885-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Menkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin concentrations, leading to multiple abnormalities in the whole-body, especially in connective tissue and central nervous system. However, serum copper and ceruloplasmin levels are not reliable diagnostic biomarkers due to the low concentrations in healthy newborns either. The featured imaging manifestations play an important role in diagnosing Menkes disease. To our knowledge, there are few reports on the systemic imaging manifestations of Menkes disease. CASE PRESENTATION A 4-month-old male patient presented with recurrent seizures. He had cognitive, intellectual, growth, gross motor, precision movement, and language developmental lags. The patient's hemoglobin and serum ceruloplasmin level were low. On MRI, increased intracranial vascular tortuosity, cerebral and cerebellar atrophy, white matter changes, and basal ganglia abnormalities were observed. Plain radiograph revealed wormian bones, rib flaring, metaphyseal spurring, and periosteal reactions in the long bones of the limbs. A pathogenic variant in ATP7A gene was identified in the patient, so he was confirmed the diagnosis of Menkes disease. His symptoms did not improve despite symptomatic and supportive treatment during his hospitalization. Unfortunately, the infant died 3 months after leaving hospital. CONCLUSION A comprehensive and intuitive understanding of the disease's imaging manifestations can help clinicians to identify the disease and avoid delays in care.
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Affiliation(s)
- Juncheng Zhu
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
- Department of Radiology, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, 610213, Sichuan Province, People's Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Yi Liao
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Xuesheng Li
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Fenglin Jia
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Xinmao Ma
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Haibo Qu
- Department of Radiology, West China Second University Hospital of Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China.
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Ruturaj, Mishra M, Saha S, Maji S, Rodriguez-Boulan E, Schreiner R, Gupta A. Regulation of the apico-basolateral trafficking polarity of the homologous copper-ATPases ATP7A and ATP7B. J Cell Sci 2024; 137:jcs261258. [PMID: 38032054 PMCID: PMC10729821 DOI: 10.1242/jcs.261258] [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: 04/19/2023] [Accepted: 10/05/2023] [Indexed: 12/01/2023] Open
Abstract
The homologous P-type copper-ATPases (Cu-ATPases) ATP7A and ATP7B are the key regulators of copper homeostasis in mammalian cells. In polarized epithelia, upon copper treatment, ATP7A and ATP7B traffic from the trans-Golgi network (TGN) to basolateral and apical membranes, respectively. We characterized the sorting pathways of Cu-ATPases between TGN and the plasma membrane and identified the machinery involved. ATP7A and ATP7B reside on distinct domains of TGN in limiting copper conditions, and in high copper, ATP7A traffics to basolateral membrane, whereas ATP7B traverses common recycling, apical sorting and apical recycling endosomes en route to apical membrane. Mass spectrometry identified regulatory partners of ATP7A and ATP7B that include the adaptor protein-1 complex. Upon knocking out pan-AP-1, sorting of both Cu-ATPases is disrupted. ATP7A loses its trafficking polarity and localizes on both apical and basolateral surfaces in high copper. By contrast, ATP7B loses TGN retention but retained its trafficking polarity to the apical domain, which became copper independent. Using isoform-specific knockouts, we found that the AP-1A complex provides directionality and TGN retention for both Cu-ATPases, whereas the AP-1B complex governs copper-independent trafficking of ATP7B solely. Trafficking phenotypes of Wilson disease-causing ATP7B mutants that disrupts putative ATP7B-AP1 interaction further substantiates the role of AP-1 in apical sorting of ATP7B.
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Affiliation(s)
- Ruturaj
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
| | - Monalisa Mishra
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
| | - Soumyendu Saha
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
| | - Saptarshi Maji
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
| | - Enrique Rodriguez-Boulan
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ryan Schreiner
- Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Arnab Gupta
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India
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Chen B, Yu P, Chan WN, Xie F, Zhang Y, Liang L, Leung KT, Lo KW, Yu J, Tse GMK, Kang W, To KF. Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets. Signal Transduct Target Ther 2024; 9:6. [PMID: 38169461 PMCID: PMC10761908 DOI: 10.1038/s41392-023-01679-y] [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: 05/27/2023] [Revised: 09/15/2023] [Accepted: 10/10/2023] [Indexed: 01/05/2024] Open
Abstract
Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc's involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc's cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.
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Affiliation(s)
- Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Peiyao Yu
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Fuda Xie
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Yigan Zhang
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Kam Tong Leung
- Department of Pediatrics, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Gary M K Tse
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
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11
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Jeong J, Hwang YE, Lee M, Keum S, Song S, Kim JW, Choi JH, Rhee S. Downregulation of AP1S1 causes the lysosomal degradation of EGFR in non-small cell lung cancer. J Cell Physiol 2023; 238:2335-2347. [PMID: 37659097 DOI: 10.1002/jcp.31112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/28/2023] [Accepted: 07/13/2023] [Indexed: 09/04/2023]
Abstract
Matrix stiffness has been shown to play a critical role in cancer progression by influencing various cellular processes, including epidermal growth factor (EGF) signaling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1), a component of adaptor protein complex-1, in the regulation of EGF receptor (EGFR) intracellular trafficking during cancer cell progression. We found that AP1S1 expression was upregulated under stiff matrix conditions, resulting in the regulation of EGFR trafficking in non-small cell lung adenocarcinoma cells. Knockout of AP1S1 caused the lysosomal degradation of EGFR, leading to suppressed EGF-induced anaplastic lymphoma receptor tyrosine kinase phosphorylation. In addition, the downregulation of AP1S1 increased the sensitivity of H1975 cancer cells, which are resistant to tyrosine kinase inhibitors, to erlotinib. Collectively, our results suggest that AP1S1 could regulate EGFR recycling under stiff matrix conditions, and AP1S1 inhibition could be a novel strategy for treating cancer cells resistant to EGFR-targeted anticancer drugs.
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Affiliation(s)
- Jangho Jeong
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Ye Eun Hwang
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Minwoo Lee
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Seula Keum
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Seongeun Song
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Jee-Hye Choi
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
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12
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Affiliation(s)
- Eve A Roberts
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
| | - Michael L Schilsky
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
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13
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Moller-Hansen A, Hejla D, Lee HK, Lyles JB, Yang Y, Chen K, Li WL, Thomas G, Boerkoel CF. Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability? Am J Med Genet A 2023; 191:2181-2187. [PMID: 37141437 PMCID: PMC10524240 DOI: 10.1002/ajmg.a.63232] [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: 01/18/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023]
Abstract
To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.
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Affiliation(s)
- Ashley Moller-Hansen
- Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada
| | - Duha Hejla
- Department of Pediatrics, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada
| | - Hyun Kyung Lee
- Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada
| | - Jenea Barbara Lyles
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yunhan Yang
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Kun Chen
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Gary Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Cornelius F Boerkoel
- Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada
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14
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Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of monogenic intestinal epithelial disorders. Hum Genet 2023; 142:613-654. [PMID: 36422736 PMCID: PMC10182130 DOI: 10.1007/s00439-022-02501-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/23/2022] [Indexed: 11/27/2022]
Abstract
Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.
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Affiliation(s)
- Stephen J Babcock
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - David Flores-Marin
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Jay R Thiagarajah
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA.
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15
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Babcock S, Calvo KR, Hasserjian RP. Pediatric myelodysplastic syndrome. Semin Diagn Pathol 2023; 40:152-171. [PMID: 37173164 DOI: 10.1053/j.semdp.2023.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023]
Affiliation(s)
| | - Katherine R Calvo
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
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16
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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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17
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Garza NM, Swaminathan AB, Maremanda KP, Zulkifli M, Gohil VM. Mitochondrial copper in human genetic disorders. Trends Endocrinol Metab 2023; 34:21-33. [PMID: 36435678 PMCID: PMC9780195 DOI: 10.1016/j.tem.2022.11.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/28/2022] [Accepted: 11/04/2022] [Indexed: 11/24/2022]
Abstract
Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics.
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Affiliation(s)
- Natalie M Garza
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Abhinav B Swaminathan
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Krishna P Maremanda
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Mohammad Zulkifli
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
| | - Vishal M Gohil
- Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA.
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18
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Dwiecki PM, Wróblewska KB, Krzywańska J, Parmonik A, Muszalska-Kolos I. Critical Points in the Methodology of Preparing Copper (II) Histidinate Injections and their Quality Assessment Applying Color Measurement. J Pharm Sci 2022; 111:2471-2480. [PMID: 35341720 DOI: 10.1016/j.xphs.2022.03.015] [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: 01/14/2022] [Revised: 03/21/2022] [Accepted: 03/21/2022] [Indexed: 11/22/2022]
Abstract
Copper (II) histidinate injection solution, applied in Menkes disease treatment, is characterized by low stability due to sensitivity to oxidation. The aim of this article was to determine the critical points of the injection preparation procedure, taking into account selection of appropriate packaging, determining the solution pH or application of an excess of L-histidine. In order to assess the stability of the Cu(His)2 complex, the spectrophotometric method (VIS: 400-800 nm), and the colorimetric method using a reflectance colorimeter were applied. The color changes observed using the CIELAB color system made it possible to determine: the differences in the observed color (ΔΕ) and the color chroma (C*) and hue (h°). It was found that the following parameters: λmax and ΔE enable fast and objective assessment of copper (II) histidinate injection solution quality. The advantage of the colorimetric method is the non-invasiveness of the analysis which is performed through the packaging material (transparent vial). The developed methodology of preparing Cu(His)2 injections in hospitals or community pharmacies guarantees their stability for at least 6 months, provided that the solution is stored at lower temperatures (2-8°C or 4°C).
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Affiliation(s)
- Piotr Mariusz Dwiecki
- Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland; Pharmaceutical Company "Ziołolek" Sp. z o.o., Starołęcka 189, 61-341 Poznań, Poland
| | - Katarzyna Barbara Wróblewska
- Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
| | - Justyna Krzywańska
- Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
| | - Agata Parmonik
- Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland
| | - Izabela Muszalska-Kolos
- Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland.
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19
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Duncan MC. New directions for the clathrin adaptor AP-1 in cell biology and human disease. Curr Opin Cell Biol 2022; 76:102079. [DOI: 10.1016/j.ceb.2022.102079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 11/03/2022]
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20
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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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21
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Mechanisms regulating the sorting of soluble lysosomal proteins. Biosci Rep 2022; 42:231123. [PMID: 35394021 PMCID: PMC9109462 DOI: 10.1042/bsr20211856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022] Open
Abstract
Lysosomes are key regulators of many fundamental cellular processes such as metabolism, autophagy, immune response, cell signalling and plasma membrane repair. These highly dynamic organelles are composed of various membrane and soluble proteins, which are essential for their proper functioning. The soluble proteins include numerous proteases, glycosidases and other hydrolases, along with activators, required for catabolism. The correct sorting of soluble lysosomal proteins is crucial to ensure the proper functioning of lysosomes and is achieved through the coordinated effort of many sorting receptors, resident ER and Golgi proteins, and several cytosolic components. Mutations in a number of proteins involved in sorting soluble proteins to lysosomes result in human disease. These can range from rare diseases such as lysosome storage disorders, to more prevalent ones, such as Alzheimer’s disease, Parkinson’s disease and others, including rare neurodegenerative diseases that affect children. In this review, we discuss the mechanisms that regulate the sorting of soluble proteins to lysosomes and highlight the effects of mutations in this pathway that cause human disease. More precisely, we will review the route taken by soluble lysosomal proteins from their translation into the ER, their maturation along the Golgi apparatus, and sorting at the trans-Golgi network. We will also highlight the effects of mutations in this pathway that cause human disease.
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22
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Zheng D, Fu W, Jin L, Jiang X, Jiang W, Guan Y, Hao R. The Overexpression and Clinical Significance of AP1S1 in Breast Cancer. Cancer Manag Res 2022; 14:1475-1492. [PMID: 35463798 PMCID: PMC9021008 DOI: 10.2147/cmar.s346519] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 03/24/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose To explore the mechanism of AP1S1 in breast cancer. Methods and Results In different datasets, we found that AP1S1 is more highly expressed in breast tumors, which was furthermore verified in our local cohort.Immune infiltration analysis showed that AP1S1 was related to a variety of immune cells. The higher AP1S1 expression was negatively correlated with a variety of immune infiltrating cells, suggesting that AP1S1 may affect cellular immunity.Clinical analysis showed that patients with higher AP1S1 expression had higher estrogen receptor gene expression and were more prone to distant metastasis and lymph node metastasis.The overall survival rate, disease-specific survival rate, and progression-free interval time were worse in the group with higher AP1S1 expression. AP1S1 may be a potential oncogene of breast cancer, and overexpression is related to the poor prognosis of breast cancer.Therefore, a nomogram was constructed, along with correlated gene analysis and functional analysis to further explore the carcinogenic mechanism, practical clinical issues, and value of AP1S1. Conclusion AP1S1 is a potential oncogene of breast cancer.
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Affiliation(s)
- Danni Zheng
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Weida Fu
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Lingli Jin
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Xiaofang Jiang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Wenjie Jiang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Yaoyao Guan
- Department of Plastic Surgery, Sir Run-Run Hospital Affiliated to Zhejiang University, Hangzhou, People’s Republic of China
- Correspondence: Yaoyao Guan, 3 Qingchun East Road, Jianggan District, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 571-86006618, Fax +86 571-86044817, Email
| | - Rutian Hao
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
- Rutian Hao, South White Elephant Warm hospital first New Area, Ouhai District, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 577 5557, Fax +86 577-55578033, Email
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23
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Faghihi F, Khamirani HJ, Zoghi S, Kamal N, Yeganeh BS, Dianatpour M, Bagher Tabei SM, Dastgheib SA. Phenotypic spectrum of autosomal recessive Keratitis-Ichthyosis-Deafness Syndrome (KIDAR) due to mutations in AP1B1. Eur J Med Genet 2022; 65:104449. [PMID: 35144013 DOI: 10.1016/j.ejmg.2022.104449] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 11/19/2021] [Accepted: 02/06/2022] [Indexed: 11/19/2022]
Abstract
Inborn errors in copper metabolism result in a diverse set of abnormalities such as Wilson disease and MEDNIK syndrome. Homozygous pathogenic variants in AP1B1 lead to KIDAR (Keratitis-Ichthyosis-Deafness Syndrome). The main phenotypic features of KIDAR are ichthyosis, keratitis, erythroderma, and progressive hearing loss accompanied by developmental delay and failure to thrive. Herein, we describe a six-and-a-half-year-old boy with KIDAR caused by a novel pathogenic variant in AP1B1 (NM_001127.4:c.1263C > A, p.Tyr421*). The proband presented with ichthyosis, erythroderma, palmoplantar keratoderma, hearing loss, and corneal scarring. He also had hypotonia, global developmental delay, and photophobia. Lastly, we review all of the previously reported cases and the clinical features associated with KIDAR.
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Affiliation(s)
- Fatemeh Faghihi
- Department of Biology, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Hossein Jafari Khamirani
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran; Comprehensive Medical Genetic Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sina Zoghi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Kamal
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Babak Shirazi Yeganeh
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehdi Dianatpour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Bagher Tabei
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran; Maternal-Fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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24
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Pallares RM, An DD, Hébert S, Faulkner D, Loguinov A, Proctor M, Villalobos JA, Bjornstad KA, Rosen CJ, Vulpe C, Abergel RJ. Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium. Mol Omics 2022; 18:237-248. [PMID: 35040455 DOI: 10.1039/d1mo00267h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with Saccharomyces cerevisiae. Furthermore, we determine which mechanisms are conserved in humans, and their implications for diseases related to the use of gadolinium-based contrast agents in medicine. A homozygous deletion pool of 4291 strains were screened to identify biological functions and pathways disturbed by the metal. Gene ontology and pathway enrichment analyses showed endocytosis and vesicle-mediated transport as the main yeast response to gadolinium, while certain metabolic processes, such as glycosylation, were the primary disrupted functions after the metal treatments. Cluster and protein-protein interaction network analyses identified proteins mediating vesicle-mediated transport through the Golgi apparatus and the vacuole, and vesicle cargo exocytosis as key components to reduce the metal toxicity. Moreover, the metal seemed to induce cytotoxicity by disrupting the function of enzymes (e.g. transferases and proteases) and chaperones involved in metabolic processes. Several of the genes and proteins associated with gadolinium toxicity are conserved in humans, suggesting that they may participate in pathologies linked to gadolinium-based contrast agent exposures. We thereby discuss the potential role of these conserved genes and gene products in gadolinium-induced nephrogenic systemic fibrosis, and propose potential prophylactic strategies to prevent its adverse health effects.
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Affiliation(s)
- Roger M Pallares
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Dahlia D An
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Solène Hébert
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - David Faulkner
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Alex Loguinov
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Michael Proctor
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Jonathan A Villalobos
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Kathleen A Bjornstad
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Chris J Rosen
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
| | - Christopher Vulpe
- Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA
| | - Rebecca J Abergel
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. .,Department of Nuclear Engineering, University of California, Berkeley, CA, 94720, USA
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25
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Matakovic L, Overeem AW, Klappe K, van IJzendoorn SCD. Induction of Bile Canaliculi-Forming Hepatocytes from Human Pluripotent Stem Cells. Methods Mol Biol 2022; 2544:71-82. [PMID: 36125710 DOI: 10.1007/978-1-0716-2557-6_4] [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] [Indexed: 06/15/2023]
Abstract
Cell polarity and formation of bile canaliculi can be achieved in hepatocytes which are generated from patient-derived induced pluripotent stem cells. This allows for the study of endogenous mutant proteins, patient-specific pathogenesis, and drug responses for diseases where hepatocyte polarity and bile canaliculi play a key role. Here, we describe a step-by-step protocol for the generation of bile canaliculi-forming hepatocytes from induced pluripotent stem cells and their evaluation.
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Affiliation(s)
- Lavinija Matakovic
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arend W Overeem
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
| | - Karin Klappe
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Sven C D van IJzendoorn
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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26
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Wen MH, Xie X, Huang PS, Yang K, Chen TY. Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system. Open Biol 2021; 11:210128. [PMID: 34847776 PMCID: PMC8633785 DOI: 10.1098/rsob.210128] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Imbalanced copper homeostasis and perturbation of membrane trafficking are two common symptoms that have been associated with the pathogenesis of neurodegenerative and neurodevelopmental diseases. Accumulating evidence from biophysical, cellular and in vivo studies suggest that membrane trafficking orchestrates both copper homeostasis and neural functions-however, a systematic review of how copper homeostasis and membrane trafficking interplays in neurons remains lacking. Here, we summarize current knowledge of the general trafficking itineraries for copper transporters and highlight several critical membrane trafficking regulators in maintaining copper homeostasis. We discuss how membrane trafficking regulators may alter copper transporter distribution in different membrane compartments to regulate intracellular copper homeostasis. Using Parkinson's disease and MEDNIK as examples, we further elaborate how misregulated trafficking regulators may interplay parallelly or synergistically with copper dyshomeostasis in devastating pathogenesis in neurodegenerative diseases. Finally, we explore multiple unsolved questions and highlight the existing challenges to understand how copper homeostasis is modulated through membrane trafficking.
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Affiliation(s)
- Meng-Hsuan Wen
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Xihong Xie
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Pei-San Huang
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
| | - Karen Yang
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Tai-Yen Chen
- Department of Chemistry, University of Houston, Houston, TX 77204, USA
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27
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Copper in tumors and the use of copper-based compounds in cancer treatment. J Inorg Biochem 2021; 226:111634. [PMID: 34740035 DOI: 10.1016/j.jinorgbio.2021.111634] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
Copper homeostasis is strictly regulated by protein transporters and chaperones, to allow its correct distribution and avoid uncontrolled redox reactions. Several studies address copper as involved in cancer development and spreading (epithelial to mesenchymal transition, angiogenesis). However, being endogenous and displaying a tremendous potential to generate free radicals, copper is a perfect candidate, once opportunely complexed, to be used as a drug in cancer therapy with low adverse effects. Copper ions can be modulated by the organic counterpart, after complexed to their metalcore, either in redox potential or geometry and consequently reactivity. During the last four decades, many copper complexes were studied regarding their reactivity toward cancer cells, and many of them could be a drug choice for phase II and III in cancer therapy. Also, there is promising evidence of using 64Cu in nanoparticles as radiopharmaceuticals for both positron emission tomography (PET) imaging and treatment of hypoxic tumors. However, few compounds have gone beyond testing in animal models, and none of them got the status of a drug for cancer chemotherapy. The main challenge is their solubility in physiological buffers and their different and non-predictable mechanism of action. Moreover, it is difficult to rationalize a structure-based activity for drug design and delivery. In this review, we describe the role of copper in cancer, the effects of copper-complexes on tumor cell death mechanisms, and point to the new copper complexes applicable as drugs, suggesting that they may represent at least one component of a multi-action combination in cancer therapy.
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28
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Lachowicz JI, Lecca LI, Meloni F, Campagna M. Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy. Molecules 2021; 26:6639. [PMID: 34771058 PMCID: PMC8587420 DOI: 10.3390/molecules26216639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 01/13/2023] Open
Abstract
An increasing number of pathologies correlates with both toxic and essential metal ions dyshomeostasis. Next to known genetic disorders (e.g., Wilson's Disease and β-Thalassemia) other pathological states such as neurodegeneration and diabetes are characterized by an imbalance of essential metal ions. Metal ions can enter the human body from the surrounding environment in the form of free metal ions or metal-nanoparticles, and successively translocate to different tissues, where they are accumulated and develop distinct pathologies. There are no characteristic symptoms of metal intoxication, and the exact diagnosis is still difficult. In this review, we present metal-related pathologies with the most common onsets, biomarkers of metal intoxication, and proper techniques of metal qualitative and quantitative analysis. We discuss the possible role of drugs with metal-chelating ability in metal dyshomeostasis, and present recent advances in therapies of metal-related diseases.
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Affiliation(s)
| | | | | | - Marcello Campagna
- Division of Occupational Medicine, Department of Medical Sciences and Public Health, University of Cagliari, 09048 Monserrato, CA, Italy; (J.I.L.); (L.I.L.); (F.M.)
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29
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Zhang YZ, Jian G, He P, Yu R, Tian M, Wu Y, Zhang BR. Immunoglobulin a nephropathy as the first clinical presentation of Wilson disease: a case report and literature review. BMC Gastroenterol 2021; 21:384. [PMID: 34666712 PMCID: PMC8524855 DOI: 10.1186/s12876-021-01954-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/04/2021] [Indexed: 11/10/2022] Open
Abstract
Background Wilson disease (WD) is a rare genetic disorder of copper metabolism. Differences in copper tissue accumulation lead to various clinical manifestations, including some atypical presentations. The complex clinical features of WD make diagnosis challenging, delaying the best chance for treatment. Case presentation We report a case of a 26-year-old man with nephritis-range proteinuria and elevated serum creatinine. The renal pathology indicated immunoglobulin A (IgA) nephropathy and tubular injury, which was inconsistent with glomerular lesions. Cirrhosis was also detected by imaging examination. Considering both kidney injury and liver damage, WD was suspected. Based on results showing abnormal copper metabolism, corneal Kayser–Fleischer rings, and genetic disorders in the ATP7B gene, the patient was finally diagnosed with WD. After treatment with oral penicillamine, zinc sulfate and losartan, the patient showed alleviation of both WD and nephropathy after 3 years of follow-up. He maintained a good quality of daily life. Conclusion This case highlights that unexplained neurological and liver symptoms in patients with IgA nephropathy can be clues for WD.
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Affiliation(s)
- Yong-Zhe Zhang
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China
| | - Geng Jian
- Department of Pathology, School of Basic Medica Sciences, Southern Medical University, 1838, North Guangzhou Avenue, Guangzhou, 510515, China
| | - Ping He
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China
| | - Rui Yu
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China
| | - Mi Tian
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China
| | - Yan Wu
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China
| | - Bei-Ru Zhang
- Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, China.
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30
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McCray BA, Scherer SS. Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities. Neurotherapeutics 2021; 18:2269-2285. [PMID: 34606075 PMCID: PMC8804038 DOI: 10.1007/s13311-021-01099-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2021] [Indexed: 01/12/2023] Open
Abstract
Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.
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Affiliation(s)
- Brett A. McCray
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA
| | - Steven S. Scherer
- Department of Neurology, The University of Pennsylvania, Philadelphia, PA 19104 USA
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31
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Squitti R, Faller P, Hureau C, Granzotto A, White AR, Kepp KP. Copper Imbalance in Alzheimer's Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology. J Alzheimers Dis 2021; 83:23-41. [PMID: 34219710 DOI: 10.3233/jad-201556] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.
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Affiliation(s)
- Rosanna Squitti
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Peter Faller
- Institut de Chimie, UMR 7177, CNRS, Université de Strasbourg, Strasbourg, France
| | | | - Alberto Granzotto
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.,Center for Advanced Sciences and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy.,Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), Laboratory of Molecular Neurology, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy
| | - Anthony R White
- Mental Health Program, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia
| | - Kasper P Kepp
- DTU Chemistry, Technical University of Denmark, Lyngby, Denmark
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32
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Sánchez-Monteagudo A, Ripollés E, Berenguer M, Espinós C. Wilson's Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines 2021; 9:1100. [PMID: 34572285 PMCID: PMC8471362 DOI: 10.3390/biomedicines9091100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/20/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD's phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.
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Affiliation(s)
- Ana Sánchez-Monteagudo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Edna Ripollés
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
| | - Marina Berenguer
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
- Department of Medicine, Universitat de València, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain; (A.S.-M.); (E.R.)
- Joint Unit on Rare Diseases CIPF-IIS La Fe, 46012 Valencia, Spain;
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33
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Hamie L, Eid E, Khalil S, Ghaoui N, Abbas O, Hamie M, Akl PA, Kurban M. Genodermatoses with hearing impairment. J Am Acad Dermatol 2021; 85:931-944. [PMID: 34153387 DOI: 10.1016/j.jaad.2021.06.850] [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: 01/11/2021] [Revised: 03/14/2021] [Accepted: 06/15/2021] [Indexed: 10/21/2022]
Abstract
Hearing loss is a prominent feature in multiple genodermatoses. Underappreciation of auditory deficits can misdirect proper diagnosis by the treating dermatologist. This review reviews the anatomic, developmental, and embryologic aspects that characterize the ear and summarizes genodermatoses that have aberrant auditory findings. The latter are classified into neural crest, metabolic, pigmentary, craniofacial, and a miscellaneous category of disorders lacking specific cutaneous findings. The algorithms provided in this review enable treating dermatologists to better recognize and manage genodermatoses with ear involvement.
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Affiliation(s)
- Lamiaa Hamie
- Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon
| | - Edward Eid
- Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon
| | - Samar Khalil
- Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon
| | - Nohra Ghaoui
- Department of Internal Medicine, American University of Beirut Medical Centre, Beirut, Lebanon
| | - Ossama Abbas
- Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon
| | | | | | - Mazen Kurban
- Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon; Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon; Division of Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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34
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Fanni D, Gerosa C, Nurchi VM, Cappai R, Mureddu M, Eyken PV, Saba L, Manchia M, Faa G. Copper-Induced Epigenetic Changes Shape the Clinical Phenotype in Wilson's Disease. Curr Med Chem 2021; 28:2707-2716. [PMID: 32744959 DOI: 10.2174/0929867327666200730214757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 11/22/2022]
Abstract
Wilson's disease is a congenital disorder of copper metabolism whose pathogenesis remains, at least in part, unknown. Subjects carrying the same genotype may show completely different phenotypes, differing for the age at illness onset or for the hepatic, neurologic or psychiatric clinical presentation. The inability to find a unequivocal correlation between the type of mutation in the ATPase copper transporting beta (ATP7B) gene and the phenotypic manifestation, has encouraged many authors to look for epigenetic factors interacting with the genetic changes. Here, the evidences regarding the ability of copper overload to change the global DNA methylation status are discussed.
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Affiliation(s)
- Daniela Fanni
- Section of Pathology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Clara Gerosa
- Section of Pathology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Valeria Marina Nurchi
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Rosita Cappai
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Marta Mureddu
- Section of Pathology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Peter Van Eyken
- Department of Pathology, UZ Genk Regional Hospital, Genk, Belgium
| | - Luca Saba
- Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), Cagliari, Italy
| | - Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Gavino Faa
- Section of Pathology, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
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35
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Debs S, Ferreira CR, Groden C, Kim HJ, King KA, King MC, Lehky T, Cowen EW, Brown LH, Merideth M, Owen CM, Macnamara E, Toro C, Gahl WA, Soldatos A. Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy. Am J Med Genet A 2021; 185:2102-2107. [PMID: 34089226 DOI: 10.1002/ajmg.a.62245] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/09/2020] [Accepted: 11/14/2020] [Indexed: 11/07/2022]
Abstract
A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.
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Affiliation(s)
- Sarah Debs
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.,Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Carlos R Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Catherine Groden
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - H Jeffrey Kim
- National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA
| | - Kelly A King
- National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA
| | - Monique C King
- Rehabilitation Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
| | - Tanya Lehky
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Edward W Cowen
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Laura H Brown
- Johns Hopkins Community Physicians_North Bethesda, Rockville, MD, USA
| | - Melissa Merideth
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Carter M Owen
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ellen Macnamara
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Camilo Toro
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - William A Gahl
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ariane Soldatos
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
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36
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Shur NE, Summerlin ML, McIntosh BJ, Shalaby-Rana E, Hinds TS. Genetic causes of fractures and subdural hematomas: fact versus fiction. Pediatr Radiol 2021; 51:1029-1043. [PMID: 33999244 DOI: 10.1007/s00247-020-04865-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/19/2020] [Accepted: 09/30/2020] [Indexed: 10/21/2022]
Abstract
Genetic disorders are in the differential diagnosis when young children present with unexplained fractures or intracranial hemorrhage. For medical and legal reasons, it is imperative to make the correct diagnosis and provide clear, evidence-based explanations of how alternative diagnoses were ruled out. A genetics consultation in cases of suspected child physical abuse should synthesize the history of present illness, medical history, family history, physical examination, and radiologic and laboratory findings in consultation with other specialists. The medical geneticist highlights how these disorders truly present. When the natural history of a genetic disorder is understood, it becomes clear that genetic disorders are not mysterious or difficult to diagnose. As highlighted in this case-based review, mainstream medical practice allows for differentiation among the intracranial and skeletal manifestations of osteogenesis imperfecta, Menkes disease, glutaric acidemia type 1 and child physical abuse. This review also highlights how a genetic disorder, Ehlers-Danlos syndrome, can be misused in a courtroom. Finally, this review summarizes when genetic testing is appropriate in cases of suspected child physical abuse.
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Affiliation(s)
- Natasha E Shur
- Rare Disease Institute, Division of Genetics and Metabolism, Children's National Hospital, 111 Michigan Ave., NW, Washington, DC, 20010, USA. .,George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
| | - Maxwell L Summerlin
- George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Bruce J McIntosh
- Child Protection Team System, Children's Medical Service, Florida Department of Health, Tallahassee, FL, USA
| | - Eglal Shalaby-Rana
- George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Diagnostic Imaging and Radiology, Children's National Hospital, Washington, DC, USA
| | - Tanya S Hinds
- George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Child & Adolescent Protection Center, Children's National Hospital, Washington, DC, USA
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Diamanti A, Calvitti G, Martinelli D, Santariga E, Capriati T, Bolasco G, Iughetti L, Pujia A, Knafelz D, Maggiore G. Etiology and Management of Pediatric Intestinal Failure: Focus on the Non-Digestive Causes. Nutrients 2021; 13:nu13030786. [PMID: 33673586 PMCID: PMC7997222 DOI: 10.3390/nu13030786] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 02/24/2021] [Indexed: 12/20/2022] Open
Abstract
Background: Intestinal failure (IF) is defined as reduction in functioning gut mass below the minimal amount necessary for adequate digestion and absorption. In most cases, IF results from intrinsic diseases of the gastrointestinal tract (digestive IF) (DIF); few cases arise from digestive vascular components, gut annexed (liver and pancreas) and extra-digestive organs or from systemic diseases (non-digestive IF) (NDIF). The present review revised etiology and treatments of DIF and NDIF, with special focus on the pathophysiological mechanisms, whereby NDIF develops. Methods: We performed a comprehensive search of published literature from January 2010 to the present by selecting the following search strings: “intestinal failure” OR “home parenteral nutrition” OR “short bowel syndrome” OR “chronic pseudo-obstruction” OR “chronic intestinal pseudo-obstruction” OR “autoimmune enteropathy” OR “long-term parenteral nutrition”. Results: We collected overall 1656 patients with well-documented etiology of IF: 1419 with DIF (86%) and 237 with NDIF (14%), 55% males and 45% females. Among DIF cases, 66% had SBS and among NDIF cases 90% had malabsorption/maldigestion. Conclusions: The improved availability of diagnostic and therapeutic tools has increased prevalence and life expectancy of rare and severe diseases responsible for IF. The present review greatly expands the spectrum of knowledge on the pathophysiological mechanisms through which the diseases not strictly affecting the intestine can cause IF. In view of the rarity of the majority of pediatric IF diseases, the development of IF Registries is strongly required; in fact, through information flow within the network, the Registries could improve IF knowledge and management.
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Affiliation(s)
- Antonella Diamanti
- Hepatology Gastroenterology and Nutrition Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy; (T.C.); (G.B.); (D.K.); (G.M.)
- Correspondence: ; Tel.: +39-0668592189
| | - Giacomo Calvitti
- Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy; (G.C.); (L.I.)
| | - Diego Martinelli
- Metabolic Diseases Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy;
| | - Emma Santariga
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (E.S.); (A.P.)
| | - Teresa Capriati
- Hepatology Gastroenterology and Nutrition Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy; (T.C.); (G.B.); (D.K.); (G.M.)
| | - Giulia Bolasco
- Hepatology Gastroenterology and Nutrition Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy; (T.C.); (G.B.); (D.K.); (G.M.)
| | - Lorenzo Iughetti
- Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, 41121 Modena, Italy; (G.C.); (L.I.)
| | - Arturo Pujia
- Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (E.S.); (A.P.)
| | - Daniela Knafelz
- Hepatology Gastroenterology and Nutrition Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy; (T.C.); (G.B.); (D.K.); (G.M.)
| | - Giuseppe Maggiore
- Hepatology Gastroenterology and Nutrition Unit, “Bambino Gesù” Children Hospital, 00165 Rome, Italy; (T.C.); (G.B.); (D.K.); (G.M.)
- Medical Sciences Department Ferrara University, 44121 Ferrara, Italy
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Mutti C, Bazzurri V, Tsantes E, Curti E, Parrino L, Granella F. Copper deficiency-associated myelopathy in cryptogenic hyperzincemia: a case report. ACTA BIO-MEDICA : ATENEI PARMENSIS 2021; 92:e2021054. [PMID: 33682842 PMCID: PMC7975935 DOI: 10.23750/abm.v92i1.9730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/12/2020] [Indexed: 11/23/2022]
Abstract
Copper deficiency syndrome is an underestimated cause of posterior myelitis. We describe the case of a 41-year-old woman, who developed a subacute ataxic paraparesis associated with low back pain. Her 3T spine MRI showed a thin hyperintense FS-Echo T2 longitudinally extensive lesion involving the posterior columns of the cervical cord (from C2 to C6). An extensive diagnostic work-up excluded other causes of myelopathy and blood tests pointed out hypocupremia and mild hyperzincemia. Patients affected by this rare form of oligoelement deficiency typically develop progressive posterior column dysfunction with sensory ataxia and spasticity, sometimes associated with sensori-motor polyneuropathy. Clinical and radiological characteristics of posterior myelopathy due to copper deficiency are briefly reviewed. Physicians should be aware of this condition since a prompt introduction of copper supplementation can avoid progression of the neurological damage. (www.actabiomedica.it)
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Affiliation(s)
| | - Veronica Bazzurri
- Neurology Unit, Department of General Medicine, University Hospital of Parma, Parma, Italy.
| | - Elena Tsantes
- Neuroscience Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.
| | - Erica Curti
- Neuroscience Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.
| | - Liborio Parrino
- Sleep Disorders Center, Department of General Medicine, University Hospital of Parma, Parma, Italy.
| | - Franco Granella
- Neurology Unit, Department of General Medicine, University Hospital of Parma, Parma, Italy.
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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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Meriç R, Ercan-Sencicek AG, Uludağ Alkaya D, Şahin Y, Sar M, Bilguvar K, Tüysüz B. A patient with mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia syndrome caused by AP1B1 gene variant. Clin Dysmorphol 2021; 30:54-57. [PMID: 32969855 DOI: 10.1097/mcd.0000000000000350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Rüya Meriç
- Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Adife Gülhan Ercan-Sencicek
- Department of Neurosurgery, Program on Neurogenetics, Yale Medical School, Yale University, New Haven, Connecticut, USA
| | - Dilek Uludağ Alkaya
- Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Yasin Şahin
- Department of Pediatric Gastroenterology, Cerrahpasa Medical School, Istanbul University - Cerrahpasa
| | - Mehmet Sar
- Department of Pathology, Cerrahpasa Medical School, Istanbul University - Cerrahpasa, Istanbul, Turkey
| | - Kaya Bilguvar
- Department of Neurosurgery, Program on Neurogenetics, Yale Medical School, Yale University, New Haven, Connecticut, USA
| | - Beyhan Tüysüz
- Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
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Shanbhag VC, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris MJ. Copper metabolism as a unique vulnerability in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118893. [PMID: 33091507 DOI: 10.1016/j.bbamcr.2020.118893] [Citation(s) in RCA: 229] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023]
Abstract
The last 25 years have witnessed tremendous progress in identifying and characterizing proteins that regulate the uptake, intracellular trafficking and export of copper. Although dietary copper is required in trace amounts, sufficient quantities of this metal are needed to sustain growth and development in humans and other mammals. However, copper is also a rate-limiting nutrient for the growth and proliferation of cancer cells. Oral copper chelators taken with food have been shown to confer anti-neoplastic and anti-metastatic benefits in animals and humans. Recent studies have begun to identify specific roles for copper in pathways of oncogenic signaling and resistance to anti-neoplastic drugs. Here, we review the general mechanisms of cellular copper homeostasis and discuss roles of copper in cancer progression, highlighting metabolic vulnerabilities that may be targetable in the development of anticancer therapies.
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Affiliation(s)
- Vinit C Shanbhag
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States of America; The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, United States of America
| | - Nikita Gudekar
- Genetics Area Program, University of Missouri, Columbia, MO 65211, United States of America; The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, United States of America
| | - Kimberly Jasmer
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States of America; The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, United States of America
| | - Christos Papageorgiou
- Department of Medicine, University of Missouri, Columbia, MO 65211, United States of America
| | - Kamal Singh
- The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, United States of America; Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, United States of America
| | - Michael J Petris
- Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States of America; Department of Ophthalmology, University of Missouri, Columbia, MO 65211, United States of America; Genetics Area Program, University of Missouri, Columbia, MO 65211, United States of America; The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO 65211, United States of America.
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Abstract
PURPOSE OF REVIEW The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms. RECENT FINDINGS Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene. SUMMARY Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.
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Affiliation(s)
- Annu Aggarwal
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Memory Clinic, KDAH
| | - Mohit Bhatt
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Movement Disorder Clinic, KDAH, Mumbai, Maharashtra, India
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Espinós C, Ferenci P. Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice? JHEP Rep 2020; 2:100114. [PMID: 32613181 PMCID: PMC7322184 DOI: 10.1016/j.jhepr.2020.100114] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 03/23/2020] [Accepted: 03/30/2020] [Indexed: 12/16/2022] Open
Abstract
The diagnosis of Wilson disease is not always easy. For many patients, a combination of tests reflecting disturbed copper metabolism may be needed. Testing for ATP7B variants has become part of the routine diagnostic approach. The methods of genetic testing include analysis of the 21 coding exons and intronic flanking sequences, in which exons with recurrent variants would be prioritised depending on the mutation frequency in the local population. If sequencing the entire ATP7B gene cannot identify 2 variants and the suspicion for Wilson disease is high, after reviewing the clinical data, WES (whole-exome sequencing) or WGS (whole-genome sequencing) could be applied. A workflow based on the type and number of ATP7B variants responsible for Wilson disease is proposed. Genetic testing is indicated for confirmation of diagnosis, family screening, and screening of newborns and infants and in unclear cases suspected of suffering from Wilson disease. However, genetic testing is not a routine screening test for Wilson disease. If no additional variants can be identified, it can be assumed that other hereditary disorders may mimic Wilson disease (congenital disorders of glycosylation, MEDNIK syndrome, idiopathic or primary copper toxicoses).
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Affiliation(s)
- Carmen Espinós
- Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
- Rare Diseases Joint Units, CIPF-IIS La Fe & INCLIVA, Valencia, Spain
- Department of Genetics, Universitat de València, Valencia, Spain
| | - Peter Ferenci
- Department of Internal Medicine 3, Gastroenterology and Hepatology, Medical University of Vienna, Austria
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AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect. Hum Genet 2020; 139:1247-1259. [PMID: 32306098 PMCID: PMC7497319 DOI: 10.1007/s00439-020-02168-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/10/2020] [Indexed: 12/16/2022]
Abstract
Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.
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Copper Does Not Induce Tenogenic Differentiation but Promotes Migration and Increases Lysyl Oxidase Activity in Adipose-Derived Mesenchymal Stromal Cells. Stem Cells Int 2020; 2020:9123281. [PMID: 32148523 PMCID: PMC7053469 DOI: 10.1155/2020/9123281] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 11/25/2019] [Accepted: 12/17/2019] [Indexed: 01/08/2023] Open
Abstract
Background Copper belongs to the essential trace metals that play a key role in the course of cellular processes maintaining the whole body's homeostasis. As there is a growing interest in transplanting mesenchymal stromal cells (MSCs) into the site of injury to improve the regeneration of damaged tendons, the purpose of the study was to verify whether copper supplementation may have a positive effect on the properties of human adipose tissue-derived MSCs (hASCs) which potentially can contribute to improvement of tendon healing. Results Cellular respiration of hASCs decreased with increasing cupric sulfate concentrations after 5 days of incubation. The treatment with CuSO4 did not positively affect the expression of genes associated with tenogenesis (COL1α1, COL3α1, MKX, and SCX). However, the level of COL1α1 protein, whose transcript was decreased in comparison to a control, was elevated after a 5-day exposition to 25 μM CuSO4. The content of the MKX and SCX protein in hASCs exposed to cupric sulfate was reduced compared to that of untreated control cells, and the level of the COL3α1 protein, whose transcript was decreased in comparison to a control, was elevated after a 5-day exposition to 25 μM CuSO4. The content of the MKX and SCX protein in hASCs exposed to cupric sulfate was reduced compared to that of untreated control cells, and the level of the COL3. Conclusion Copper sulfate supplementation can have a beneficial effect on tendon regeneration not by inducing tenogenic differentiation, but by improving the recruitment of MSCs to the site of injury, where they can secrete growth factors, cytokines and chemokines, and prevent the effects of oxidative stress at the site of inflammation, as well as improve the stabilization of collagen fibers, thereby accelerating the process of tendon healing.
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Genetic Disorders Associated with Metal Metabolism. Cells 2019; 8:cells8121598. [PMID: 31835360 PMCID: PMC6952812 DOI: 10.3390/cells8121598] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/12/2022] Open
Abstract
Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal metabolism. Some disorders have moderate to severe clinical consequences. In severe cases, these elements accumulate in different tissues and organs, particularly the brain. As they are toxic and interfere with normal biological functions, the severity of the disorder increases. However, the human body requires a very small amount of these elements, and a deficiency of or increase in these elements can cause different genetic disorders to occur. Some of the metals discussed in the present review are copper, iron, manganese, zinc, and selenium. These elements may play a key role in the pathology and physiology of the nervous system.
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Alsaif HS, Al-Owain M, Barrios-Llerena ME, Gosadi G, Binamer Y, Devadason D, Ravenscroft J, Suri M, Alkuraya FS. Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome. Am J Hum Genet 2019; 105:1016-1022. [PMID: 31630791 DOI: 10.1016/j.ajhg.2019.09.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 09/17/2019] [Indexed: 01/16/2023] Open
Abstract
MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is an autosomal-recessive disorder caused by bi-allelic mutations in AP1S1, encoding the small σ subunit of the AP-1 complex. Central to the pathogenesis of MEDNIK syndrome is abnormal AP-1-mediated trafficking of copper transporters; this abnormal trafficking results in a hybrid phenotype combining the copper-deficiency-related characteristics of Menkes disease and the copper-toxicity-related characteristics of Wilson disease. We describe three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1, encoding the large β subunit of the AP-1 complex. Similar to individuals with MEDNIK syndrome, the affected individuals we report display abnormal copper metabolism, evidenced by low plasma copper and ceruloplasmin, but lack evidence of copper toxicity in the liver. Functional characterization of fibroblasts derived from affected individuals closely resembles the abnormal ATP7A trafficking described in MEDNIK syndrome both at baseline and in response to copper treatment. Taken together, our results expand the list of inborn errors of copper metabolism.
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Affiliation(s)
- Hessa S Alsaif
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
| | - Mohammad Al-Owain
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Martin E Barrios-Llerena
- Proteomics and Mass Spectrometry, Bioscience Core Labs, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia
| | - Ghada Gosadi
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
| | - Yousef Binamer
- Department of Dermatology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia
| | - David Devadason
- Department of Paediatric Gastroenterology, Nottingham Children's Hospital, Nottingham University Hospitals, Queen's Medical Centre, Nottingham NG72UH, United Kingdom
| | - Jane Ravenscroft
- Department of Paediatric Dermatology, Nottingham Children's Hospital, Nottingham University Hospitals, Queen's Medical Centre, Nottingham NG72UH, United Kingdom
| | - Mohnish Suri
- Clinical Genetics Service, Nottingham University Hospitals, City Hospital Campus, Nottingham NG51PB, United Kingdom.
| | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
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Sanger A, Hirst J, Davies AK, Robinson MS. Adaptor protein complexes and disease at a glance. J Cell Sci 2019; 132:132/20/jcs222992. [PMID: 31636158 DOI: 10.1242/jcs.222992] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Adaptor protein (AP) complexes are heterotetramers that select cargo for inclusion into transport vesicles. Five AP complexes (AP-1 to AP-5) have been described, each with a distinct localisation and function. Furthermore, patients with a range of disorders, particularly involving the nervous system, have now been identified with mutations in each of the AP complexes. In many cases this has been correlated with aberrantly localised membrane proteins. In this Cell Science at a Glance article and the accompanying poster, we summarize what is known about the five AP complexes and discuss how this helps to explain the clinical features of the different genetic disorders.
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Affiliation(s)
- Anneri Sanger
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
| | - Jennifer Hirst
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
| | - Alexandra K Davies
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
| | - Margaret S Robinson
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK
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Polishchuk RS, Polishchuk EV. From and to the Golgi - defining the Wilson disease protein road map. FEBS Lett 2019; 593:2341-2350. [PMID: 31408533 DOI: 10.1002/1873-3468.13575] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/01/2019] [Accepted: 08/08/2019] [Indexed: 11/05/2022]
Abstract
Recent studies highlight the continued growth in the identification of a variety of cellular functions that involve the Golgi apparatus. Apart from well-known membrane sorting/trafficking and glycosylation machineries, the Golgi harbors molecular platforms operating in intracellular signaling, cytoskeleton organization, and protein quality control mechanisms. One of new emerging Golgi functions consists in the regulation of copper homeostasis by coordinating the relocation and activity of copper transporters. Of these, the Cu-transporting ATPase ATP7B (known as Wilson disease protein) plays a key role in the maintenance of the Cu balance in the body via the supply of essential Cu to the systemic circulation and via elimination of excess Cu into the bile. These activities require tightly regulated shuttling of ATP7B between the Golgi and different post-Golgi compartments. Despite significant progress over recent years, a number of issues regarding ATP7B trafficking remain to be clarified. This review summarizes current views on ATP7B trafficking pathways from and to the Golgi and underscores the challenges that should be addressed to define the ATP7B trafficking routes and mechanisms in health and disease.
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Affiliation(s)
- Roman S Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy
| | - Elena V Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.,ITMO University, St. Petersburg, Russia
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50
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Abstract
Protein coats are supramolecular complexes that assemble on the cytosolic face of membranes to promote cargo sorting and transport carrier formation in the endomembrane system of eukaryotic cells. Several types of protein coats have been described, including COPI, COPII, AP-1, AP-2, AP-3, AP-4, AP-5, and retromer, which operate at different stages of the endomembrane system. Defects in these coats impair specific transport pathways, compromising the function and viability of the cells. In humans, mutations in subunits of these coats cause various congenital diseases that are collectively referred to as coatopathies. In this article, we review the fundamental properties of protein coats and the diseases that result from mutation of their constituent subunits.
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Affiliation(s)
- Esteban C Dell'Angelica
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
| | - Juan S Bonifacino
- Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA;
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