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Wójcik-Niklewska B, Filipek E. Luscan-Lumish syndrome: A case report. World J Clin Cases 2025; 13:101471. [DOI: 10.12998/wjcc.v13.i18.101471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/25/2025] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Luscan-Lumish syndrome (LLS) is a rare genetic congenital anomaly syndrome characterised by neurodevelopmental disorders, including delayed psychomotor development, behavioral difficulties, relative or true macrocephaly and, in individual cases, ocular abnormalities. This paper aims to present the case of a child with ocular abnormalities associated with LLS.
CASE SUMMARY A 10-year-old girl born at 40 weeks gestation with features of dysmorphia, neurodevelopmental disorders, genetically confirmed LLS, convergent strabismus and suspected congenital glaucoma. Eye examination, ultrasound, optical coherence tomography (OCT), perimetry and electrophysiological study [pattern visually evoked potentials (VEP)] were performed. Best-corrected distance visual acuity was 0.5 in the right eye (correction -1.0 Dsph, -1.0 Dcyl, axis 180°) and 0.62 in the left eye (correction -2.0 Dsph). Near visual acuity (Snellen Chart) with the above correction was -0.5 D. A cycloplegic refraction test yielded -1.25 Dsph, -1.25 Dcyl, axis 165° in the right eye, and -2.0 Dsph, -0.25 Dcyl, axis 154° in the left eye. Intraocular pressure was 15 mmHg in both eyes. OCT of the maculae showed no abnormalities. In both eyes, the average ganglion cell layer and inner plexiform layer thickness was 73 μm. OCT of the optic nerve disc showed an average retinal nerve fibre layer thickness of 89 μm in the right eye and 81 μm in the left eye, with symmetry of 90%. The rim area was 1.59 mm2 and 1.74 mm2 in the right and left eye, respectively. The disc area was 2.77 mm² in the right eye and 2.89 mm2 in the left. The average cup-to-disc ratio was 0.64 in the right eye and 0.62 in the left eye. Ocular ultrasound depicted single extra echoes inside the vitreous chamber; otherwise, there were no abnormalities. Right and left eyeball lengths were 24.59 mm and 24.51 mm, respectively. Kinetic perimetry revealed no visual field defects, while static testing showed single relative scotomas. The mean defect was 4.7 dB in the right and 2.6 dB in the left eye. The loss variance values were 4.8 and 3.8 dB for the right and left eye, respectively. Pattern VEP test revealed normal values of P100 Latency. Wave amplitude in the right eye was 50% at a visual angle of 1.0° and 30% at 15’. Due to the rarity of LLS, it seems interesting to present the child ophthalmological examination with changes in the electrophysiological examination.
CONCLUSION Although eye abnormalities are infrequently described in children with LLS, the patients should undergo eye examinations, especially as they may have central nervous system anomalies that may give rise to visual impairments. Generally, children with genetically determined congenital syndromes should receive regular ophthalmic check-ups for a thorough evaluation of the eyes and prognosis of the development of visual function.
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Affiliation(s)
- Bogumiła Wójcik-Niklewska
- Department of Pediatric Ophtalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice 40-514, Silesia, Poland
- Kornel Gibiński University Clinical Centre, Medical University of Silesia in Katowice, Katowice 40-514, Silesia, Poland
| | - Erita Filipek
- Department of Pediatric Ophtalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice 40-514, Silesia, Poland
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Chen B, Zhang C, Rui H, Shen D, Huang Z, Feng W. Histone H3K36 methyltransferases NSD1 and SETD2 are required for brain development. Hum Genet 2025; 144:529-543. [PMID: 40198378 DOI: 10.1007/s00439-025-02740-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Genetic variants in two major histone H3K36 methyltransferases, NSD1 and SETD2, have been identified in patients with neurodevelopmental disorders. We examined the genetic nature of these disease-relevant variants and studied genotype-phenotype correlations using publicly available patient cohorts. To further investigate roles of Nsd1 and Setd2 in brain development, we generated mouse models with conditional knockout of Nsd1 and Setd2 in neuroepithelial cells using the Sox1-cre. Our results showed that conditional Nsd1 knockout mice were viable but exhibited reduced brain size and thinning of neocortex, while Setd2 knockout led to neonatal death with intracerebral hemorrhage and vascular abnormalities. Together, our study demonstrates new roles of Nsd1 and Setd2 in brain development.
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Affiliation(s)
- Bo Chen
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chenyang Zhang
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Huanwen Rui
- Department of Neurosurgery, Children's Hospital of Fudan University, Fudan University, Shanghai, 201102, China
| | - Dan Shen
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhuxi Huang
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weijun Feng
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China.
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Al Ojaimi M, Banimortada BJ, Alragheb A, Hajir RS, Alves C, Walid D, Raza A, El-Hattab AW. Molecular and clinical aspects of histone-related disorders. Hum Genomics 2025; 19:47. [PMID: 40301961 PMCID: PMC12042324 DOI: 10.1186/s40246-025-00734-9] [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: 12/29/2024] [Accepted: 02/20/2025] [Indexed: 05/01/2025] Open
Abstract
Epigenetics is the coordination of gene expression without alterations in the DNA sequence. Epigenetic gene expression is regulated by an intricate system that revolves around the interaction of histone proteins and DNA within the chromatin structure. Histones remain at the core of the epigenetic gene transcription regulation where histone proteins, along with the histone modification enzymes, and the subunits of chromatin remodelers and epigenetic readers play essential roles in regulating gene expression. Histone-related disorders encompass the syndromes induced by pathogenic variants in genes encoding histones, genes encoding histone modification enzymes, and genes encoding subunits of chromatin remodeler and epigenetic reader complexes. Defects in genes encoding histones lead to the expression of abnormal histone proteins. Abnormalities in genes encoding histone modification enzymes result in aberrant histone modifications. Defects in genes encoding subunits of the chromatin remodeler complexes result in defective chromatin remodeling. Defects in genes that code for the epigenetic readers (bromodomain proteins) will hinder their ability to regulate gene transcription. These disorders typically present manifestations that impact the nervous system which is particularly sensitive due to its need for specific patterns of gene expression for neural cell function and differentiation. To date, 72 histone-related disorders have been described including 7 syndromes due to defects in histone genes, 35 syndromes due to histone modifications defects, 26 syndromes due to defects in chromatin remodeling, and 4 due to defects in epigenetic readers. In this review article, the molecular basis of histone structure and function is first explained, followed by a summary of the histone-related syndromes.
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Affiliation(s)
- Mode Al Ojaimi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
- Keserwan Medical Center, Jounieh, Lebanon
| | - Bashar J Banimortada
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Abduljalil Alragheb
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Razan S Hajir
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | | | - Duaa Walid
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Afsheen Raza
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Ayman W El-Hattab
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Pediatrics, University Hospital Sharjah, Sharjah, United Arab Emirates.
- Department of Clinical Genetics, Burjeel Medical City, Abu Dhabi, United Arab Emirates.
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Lucain M, Vitobello A, Sadikovic B, Albuisson J, Gaudillat L, Chevarin M, Maraval J, Thauvin-Robinet C, Kerkhof J, Philippe C, Nambot S, Faivre L. Abnormal DNA Methylation Profile Suggests the Extension of the Clinical Spectrum of the SETD2-Related Disorders to a Syndromic Multiple Tumor Phenotype. Am J Med Genet A 2025:e64043. [PMID: 40104911 DOI: 10.1002/ajmg.a.64043] [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] [Received: 01/10/2024] [Revised: 01/27/2025] [Accepted: 02/21/2025] [Indexed: 03/20/2025]
Abstract
SETD2 has an essential role in epigenetic regulation. SETD2 pathogenic variants cause neurodevelopmental disorders (SETD2-NDDs) that most commonly include various degrees of intellectual disability and behavioral disorders, macrocephaly, brain malformations, and generalized overgrowth. A distinctive DNA methylation episignature has been identified for Luscan-Lumish syndrome. A less common phenotype, denoted SETD2-NDD with multiple congenital anomalies, failure to thrive, and profound intellectual disability, has been reported in association with a particular pathogenic variant (p.Arg1740Trp). To date, about 50 patients have been described in the literature with SETD2 causative variants. We report here an individual with a phenotype distinct from SETD2-NDDs, including normal cognition, distinctive facial features, and multiple tumor histories, including a sacral osteoblastoma at age 7, a benign femoral bone tumor at age 17, a peritoneal pseudomyxoma at age 27, and a hypophyseal macroadenoma and a low-grade optochiasmatic glioma at age 37 years. Trio exome sequencing identified a de novo heterozygous missense variant of unknown significance (p.Ser1658Leu) in the SETD2 gene. DNA methylation study by EpiSign assay confirmed the presence of an episignature profile compatible with SETD2-related disorders. Given the implication of somatic SETD2 variants in benign and malignant tumors, the implication of these SETD2 constitutional variants in tumorigenesis is discussed.
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Affiliation(s)
- Marie Lucain
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
| | - Antonio Vitobello
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
| | - Bekim Sadikovic
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, Canada, Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | | | - Léa Gaudillat
- Centre de Génétique, Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs", FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
| | - Martin Chevarin
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
| | - Julien Maraval
- Centre de Génétique, Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs", FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
| | - Christel Thauvin-Robinet
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
- Centre de Référence Maladies Rares "Déficiences Intellectuelles de Causes Rares", FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
| | - Jennifer Kerkhof
- Verspeeten Clinical Genome Centre, London Health Sciences Centre, Canada, Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Christophe Philippe
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
| | - Sophie Nambot
- Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, CHU Dijon-Bourgogne, Dijon, France
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
- Centre de Référence Maladies Rares "Déficiences Intellectuelles de Causes Rares", FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
| | - Laurence Faivre
- INSERM UMR1231 GAD, Université de Bourgogne-Franche Comté, Dijon, France
- Centre de Génétique, Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs", FHU TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
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Tibben BM, Rothbart SB. Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation. J Mol Biol 2024; 436:168394. [PMID: 38092287 PMCID: PMC10957332 DOI: 10.1016/j.jmb.2023.168394] [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: 09/28/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023]
Abstract
DNA methylation is a well-studied epigenetic modification that has key roles in regulating gene expression, maintaining genome integrity, and determining cell fate. Precisely how DNA methylation patterns are established and maintained in specific cell types at key developmental stages is still being elucidated. However, research over the last two decades has contributed to our understanding of DNA methylation regulation by other epigenetic processes. Specifically, lysine methylation on key residues of histone proteins has been shown to contribute to the allosteric regulation of DNA methyltransferase (DNMT) activities. In this review, we discuss the dynamic interplay between DNA methylation and histone lysine methylation as epigenetic regulators of genome function by synthesizing key recent studies in the field. With a focus on DNMT3 enzymes, we discuss mechanisms of DNA methylation and histone lysine methylation crosstalk in the regulation of gene expression and the maintenance of genome integrity. Further, we discuss how alterations to the balance of various sites of histone lysine methylation and DNA methylation contribute to human developmental disorders and cancers. Finally, we provide perspectives on the current direction of the field and highlight areas for continued research and development.
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Affiliation(s)
- Bailey M Tibben
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Scott B Rothbart
- Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
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Basson MA. Neurodevelopmental functions of CHD8: new insights and questions. Biochem Soc Trans 2024; 52:15-27. [PMID: 38288845 PMCID: PMC10903457 DOI: 10.1042/bst20220926] [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: 09/11/2023] [Revised: 01/03/2024] [Accepted: 01/05/2024] [Indexed: 02/29/2024]
Abstract
Heterozygous, de novo, loss-of-function variants of the CHD8 gene are associated with a high penetrance of autism and other neurodevelopmental phenotypes. Identifying the neurodevelopmental functions of high-confidence autism risk genes like CHD8 may improve our understanding of the neurodevelopmental mechanisms that underlie autism spectrum disorders. Over the last decade, a complex picture of pleiotropic CHD8 functions and mechanisms of action has emerged. Multiple brain and non-brain cell types and progenitors appear to be affected by CHD8 haploinsufficiency. Behavioural, cellular and synaptic phenotypes are dependent on the nature of the gene mutation and are modified by sex and genetic background. Here, I review some of the CHD8-interacting proteins and molecular mechanisms identified to date, as well as the impacts of CHD8 deficiency on cellular processes relevant to neurodevelopment. I endeavour to highlight some of the critical questions that still require careful and concerted attention over the next decade to bring us closer to the goal of understanding the salient mechanisms whereby CHD8 deficiency causes neurodevelopmental disorders.
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Affiliation(s)
- M. Albert Basson
- Clinical and Biomedical Sciences, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, U.K
- Centre for Craniofacial and Regenerative Biology and MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 9RT, U.K
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Lee S, Menzies L, Hay E, Ochoa E, Docquier F, Rodger F, Deshpande C, Foulds NC, Jacquemont S, Jizi K, Kiep H, Kraus A, Löhner K, Morrison PJ, Popp B, Richardson R, van Haeringen A, Martin E, Toribio A, Li F, Jones WD, Sansbury FH, Maher ER. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders. Hum Mol Genet 2023; 32:3123-3134. [PMID: 37166351 PMCID: PMC10630252 DOI: 10.1093/hmg/ddad079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 05/12/2023] Open
Abstract
Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
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Affiliation(s)
- Sunwoo Lee
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Lara Menzies
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Eleanor Hay
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Eguzkine Ochoa
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
| | - France Docquier
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Fay Rodger
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Charu Deshpande
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary’s Hospital, Manchester, UK
| | - Nicola C Foulds
- Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Sébastien Jacquemont
- CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada
- Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
| | - Khadije Jizi
- CHU Sainte-Justine Research Centre, Montreal, Quebec, Canada
| | - Henriette Kiep
- Department of Neuropediatrics, University Hospital for Children and Adolescents, Leipzig, Germany
| | - Alison Kraus
- Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
| | - Katharina Löhner
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Patrick J Morrison
- Patrick G Johnston Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
| | - Bernt Popp
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Center of Functional Genomics, Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Ruth Richardson
- Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Arie van Haeringen
- Department of Clinical Genetics, Leiden University Hospital, Leiden, The Netherlands
| | - Ezequiel Martin
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Ana Toribio
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
- Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Fudong Li
- MOE Key Laboratory for Cellular Dynamics, The School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Wendy D Jones
- Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Francis H Sansbury
- All Wales Medical Genomics Service, NHS Wales Cardiff and Vale University Health Board and Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, UK
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
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Mitchell B, Thor S, Piper M. Cellular and molecular functions of SETD2 in the central nervous system. J Cell Sci 2023; 136:jcs261406. [PMID: 37921122 DOI: 10.1242/jcs.261406] [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: 11/04/2023] Open
Abstract
The covalent modification of histones is critical for many biological functions in mammals, including gene regulation and chromatin structure. Posttranslational histone modifications are added and removed by specialised 'writer' and 'eraser' enzymes, respectively. One such writer protein implicated in a wide range of cellular processes is SET domain-containing 2 (SETD2), a histone methyltransferase that catalyses the trimethylation of lysine 36 on histone H3 (H3K36me3). Recently, SETD2 has also been found to modify proteins other than histones, including actin and tubulin. The emerging roles of SETD2 in the development and function of the mammalian central nervous system (CNS) are of particular interest as several SETD2 variants have been implicated in neurodevelopmental disorders, such as autism spectrum disorder and the overgrowth disorder Luscan-Lumish syndrome. Here, we summarise the numerous roles of SETD2 in mammalian cellular functions and development, with a focus on the CNS. We also provide an overview of the consequences of SETD2 variants in human disease and discuss future directions for understanding essential cellular functions of SETD2.
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Affiliation(s)
- Benjamin Mitchell
- The School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Stefan Thor
- The School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Michael Piper
- The School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia
- Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia
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Kumar G, Fang S, Golosova D, Lu KT, Brozoski DT, Vazirabad I, Sigmund CD. Structure and Function of RhoBTB1 Required for Substrate Specificity and Cullin-3 Ubiquitination. FUNCTION 2023; 4:zqad034. [PMID: 37575477 PMCID: PMC10413933 DOI: 10.1093/function/zqad034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 08/15/2023] Open
Abstract
We identified Rho-related BTB domain containing 1 (RhoBTB1) as a key regulator of phosphodiesterase 5 (PDE5) activity, and through PDE5, a regulator of vascular tone. We identified the binding interface for PDE5 on RhoBTB1 by truncating full-length RhoBTB1 into its component domains. Co-immunoprecipitation analyses revealed that the C-terminal half of RhoBTB1 containing its two BTB domains and the C-terminal domain (B1B2C) is the minimal region required for PDE5 recruitment and subsequent proteasomal degradation via Cullin-3 (CUL3). The C-terminal domain was essential in recruiting PDE5 as constructs lacking this region could not participate in PDE5 binding or proteasomal degradation. We also identified Pro353 and Ser363 as key amino acid residues in the B1B2C region involved in CUL3 binding to RhoBTB1. Mutation of either of these residues exhibited impaired CUL3 binding and PDE5 degradation, although the binding to PDE5 was preserved. Finally, we employed ascorbate peroxidase 2 (APEX2) proximity labeling using a B1B2C-APEX2 fusion protein as bait to capture unknown RhoBTB1 binding partners. Among several B1B2C-binding proteins identified and validated, we focused on SET domain containing 2 (SETD2). SETD2 and RhoBTB1 directly interacted, and the level of SETD2 increased in response to pharmacological inhibition of the proteasome or Cullin complex, CUL3 deletion, and RhoBTB1-inhibition with siRNA. This suggests that SETD2 is regulated by the RhoBTB1-CUL3 axis. Future studies will determine whether SETD2 plays a role in cardiovascular function.
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Affiliation(s)
- Gaurav Kumar
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shi Fang
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Daria Golosova
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ko-Ting Lu
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Daniel T Brozoski
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ibrahim Vazirabad
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Curt D Sigmund
- Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Parra A, Rabin R, Pappas J, Pascual P, Cazalla M, Arias P, Gallego-Zazo N, Santana A, Arroyo I, Artigas M, Pachajoa H, Alanay Y, Akgun-Dogan O, Ruaud L, Couque N, Levy J, Porras-Hurtado GL, Santos-Simarro F, Ballesta-Martinez MJ, Guillén-Navarro E, Muñoz-Hernández H, Nevado J, Tenorio-Castano J, Lapunzina P. Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature. Genes (Basel) 2023; 14:1179. [PMID: 37372360 DOI: 10.3390/genes14061179] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.
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Affiliation(s)
- Alejandro Parra
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Rachel Rabin
- Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
| | - John Pappas
- Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
- Clinical Genetics, NYU Orthopedic Hospital, New York, NY 10010, USA
| | - Patricia Pascual
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Mario Cazalla
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
| | - Pedro Arias
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Natalia Gallego-Zazo
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Alfredo Santana
- Clinical Genetics Unit, Complejo Hospitalario Universitario Insular-Materno Infantil de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
| | - Ignacio Arroyo
- Pediatrics Department, San Pedro de Alcántara Hospital, 10003 Cáceres, Spain
| | - Mercè Artigas
- Genetics Unit, Hospital de Navarra, 31008 Pamplona, Spain
| | - Harry Pachajoa
- Fundación Valle del Lili, Universidad Icesi, 760032 Cali, Colombia
| | - Yasemin Alanay
- Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
- Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
| | - Ozlem Akgun-Dogan
- Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
- Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
| | - Lyse Ruaud
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- INSERM UMR1141, Neurodiderot, University of Paris Cité, 75019 Paris, France
| | - Nathalie Couque
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- Laboratoire de Biologie Médicale Multisites Seqoia-FMG2025, 75014 Paris, France
| | - Jonathan Levy
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- Laboratoire de Biologie Médicale Multisites Seqoia-FMG2025, 75014 Paris, France
| | | | - Fernando Santos-Simarro
- Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitario Son Espases, Idisba, 07120 Palma de Mallorca, Spain
| | - Maria Juliana Ballesta-Martinez
- Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
| | - Encarna Guillén-Navarro
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
| | - Hugo Muñoz-Hernández
- Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8092 Zurich, Switzerland
| | - Julián Nevado
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Jair Tenorio-Castano
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
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Wu Y, Liu F, Wan R, Jiao B. A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy. Front Genet 2023; 14:1153284. [PMID: 37025455 PMCID: PMC10072282 DOI: 10.3389/fgene.2023.1153284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
Background: Luscan-Lumish syndrome is characterized by macrocephaly, postnatal overgrowth, intellectual disability (ID), developmental delay (DD), which is caused by heterozygous SETD2 (SET domain containing 2) mutations. The incidence of Luscan-Lumish syndrome is unclear. The study was conducted to provide a novel pathogenic SETD2 variant causing atypical Luscan-Lumish syndrome and review all the published SETD2 mutations and corresponding symptoms, comprehensively understanding the phenotypes and genotypes of SETD2 mutations. Methods: Peripheral blood samples of the proband and his parents were collected for next-generation sequencing including whole-exome sequencing (WES), copy number variation (CNV) detection and mitochondrial DNA sequencing. Identified variant was verified by Sanger sequencing. Conservative analysis and structural analysis were performed to investigate the effect of mutation. Public databases such as PubMed, Clinvar and Human Gene Mutation Database (HGMD) were used to collect all cases with SETD2 mutations. Results: A novel pathogenic SETD2 variant (c.5835_c.5836insAGAA, p. A1946Rfs*2) was identified in a Chinese 3-year-old boy, who had speech and motor delay without overgrowth. Conservative analysis and structural analysis showed that the novel pathogenic variant would loss the conserved domains in the C-terminal region and result in loss of function of SETD2 protein. Frameshift mutations and non-sense mutations account for 68.5% of the total 51 SETD2 point mutations, suggesting that Luscan-Lumish syndrome is likely due to loss of function of SETD2. But we failed to find an association between genotype and phenotype of SETD2 mutations. Conclusion: Our findings expand the genotype-phenotype knowledge of SETD2-associated neurological disorder and provide new evidence for further genetic counselling.
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Affiliation(s)
- Yuanyuan Wu
- Department of Reproduction and Genetics, Bethune International Peace Hospital, Shijiazhuang, China
| | - Fang Liu
- Department of Pediatrics, Bethune International Peace Hospital, Shijiazhuang, China
| | - Ruihua Wan
- Department of Pediatrics, Bethune International Peace Hospital, Shijiazhuang, China
| | - Baoquan Jiao
- Department of Reproduction and Genetics, Bethune International Peace Hospital, Shijiazhuang, China
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12
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Belanger Deloge R, Zhao X, Luna PN, Shaw CA, Rosenfeld JA, Scott DA. High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. Eur J Hum Genet 2023; 31:296-303. [PMID: 36474027 PMCID: PMC9995493 DOI: 10.1038/s41431-022-01255-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 11/04/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% vs 44.1%; p = 0.0437), suggesting that non-genetic factors may play an important role in this subset of syndromic ARM cases. Within this cohort, we identified two individuals who carried de novo pathogenic frameshift variants in ADNP, two individuals who were homozygous for pathogenic variants in BBS1, and single individuals who carried pathogenic or likely pathogenic variants in CREBBP, EP300, FANCC, KDM6A, SETD2, and SMARCA4. The association of these genes with ARMs was supported by previously published cases, and their similarity to known ARM genes as demonstrated using a machine learning algorithm. These data suggest that ES should be considered for all individuals with syndromic ARMs in whom a molecular diagnosis has not been made, and that ARMs represent a low penetrance phenotype associated with Helsmoortel-van der Aa syndrome, Bardet-Biedl syndrome 1, Rubinstein-Taybi syndromes 1 and 2, Fanconi anemia group C, Kabuki syndrome 2, SETD2-related disorders, and Coffin-Siris syndrome 4.
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Affiliation(s)
- Raymond Belanger Deloge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Xiaonan Zhao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
- Baylor Genetics, Houston, TX, USA
| | - Pamela N Luna
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chad A Shaw
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Daryl A Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.
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13
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Ritchie FD, Lizarraga SB. The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities. Front Neurosci 2023; 17:989109. [PMID: 36845425 PMCID: PMC9950662 DOI: 10.3389/fnins.2023.989109] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 01/17/2023] [Indexed: 02/12/2023] Open
Abstract
Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.
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14
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Janssen SM, Lorincz MC. Interplay between chromatin marks in development and disease. Nat Rev Genet 2022; 23:137-153. [PMID: 34608297 DOI: 10.1038/s41576-021-00416-x] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2021] [Indexed: 02/07/2023]
Abstract
DNA methylation (DNAme) and histone post-translational modifications (PTMs) have important roles in transcriptional regulation. Although many reports have characterized the functions of such chromatin marks in isolation, recent genome-wide studies reveal surprisingly complex interactions between them. Here, we focus on the interplay between DNAme and methylation of specific lysine residues on the histone H3 tail. We describe the impact of genetic perturbation of the relevant methyltransferases in the mouse on the landscape of chromatin marks as well as the transcriptome. In addition, we discuss the specific neurodevelopmental growth syndromes and cancers resulting from pathogenic mutations in the human orthologues of these genes. Integrating these observations underscores the fundamental importance of crosstalk between DNA and histone H3 methylation in development and disease.
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Affiliation(s)
- Sanne M Janssen
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Matthew C Lorincz
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
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15
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Reichard J, Zimmer-Bensch G. The Epigenome in Neurodevelopmental Disorders. Front Neurosci 2021; 15:776809. [PMID: 34803599 PMCID: PMC8595945 DOI: 10.3389/fnins.2021.776809] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/04/2021] [Indexed: 12/26/2022] Open
Abstract
Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.
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Affiliation(s)
- Julia Reichard
- Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, Aachen, Germany
| | - Geraldine Zimmer-Bensch
- Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Koenning M, Wang X, Karki M, Jangid RK, Kearns S, Tripathi DN, Cianfrocco M, Verhey KJ, Jung SY, Coarfa C, Ward CS, Kalish BT, Grimm SL, Rathmell WK, Mostany R, Dere R, Rasband MN, Walker CL, Park IY. Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice. Brain 2021; 144:2527-2540. [PMID: 34014281 PMCID: PMC8418347 DOI: 10.1093/brain/awab200] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/22/2021] [Accepted: 05/02/2021] [Indexed: 02/07/2023] Open
Abstract
Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the 'readers, writers and erasers' of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.
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Affiliation(s)
- Matthias Koenning
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xianlong Wang
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Menuka Karki
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rahul Kumar Jangid
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah Kearns
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Durga Nand Tripathi
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Michael Cianfrocco
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kristen J Verhey
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sung Yun Jung
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Cristian Coarfa
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - Christopher Scott Ward
- Molecular Physiology and Biophysics, Mouse Metabolic and Phenotyping Core, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Sandra L Grimm
- Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
| | - W Kimryn Rathmell
- Vanderbilt-Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Ricardo Mostany
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Ruhee Dere
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Cheryl Lyn Walker
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
| | - In Young Park
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA
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