Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.

Autor:	Pellerin D; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada.; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, London WC1N 3BG, UK., Méreaux JL; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Boluda S; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Danzi MC; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Dicaire MJ; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada., Davoine CS; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Genis D; Ataxia and Hereditary Spastic Paraplegia Unit, Service of Neurology, Hospital Universitari de Girona Dr. Josep Trueta (ICS) & Hospital Santa Caterina IAS, Institut d'Investigació Biomèdica de Girona (IDIBGI), 17007 Girona, Spain., Spurdens G; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Ashton C; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada.; Department of Neurology, Royal Perth Hospital, Perth, WA 6000, Australia., Hammond JM; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia., Gerhart BJ; Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8823, USA., Chelban V; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, London WC1N 3BG, UK.; Neurobiology and Medical Genetics Laboratory, 'Nicolae Testemitanu' State University of Medicine and Pharmacy, MD-2004, Chisinau, Republic of Moldova., Le PU; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada., Safisamghabadi M; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada., Yanick C; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Lee H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, London WC1N 3BG, UK., Nageshwaran SK; Department of Psychiatry, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.; Department of Neuroscience, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.; Department of Genetics and Genomic Sciences, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.; Neurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA., Matos-Rodrigues G; Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Jaunmuktane Z; Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London WC1N 3BG, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.; Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Petrecca K; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada., Akbarian S; Department of Psychiatry, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.; Department of Neuroscience, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.; Department of Genetics and Genomic Sciences, Friedman Brain Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA., Nussenzweig A; Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Usdin K; Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Renaud M; INSERM-U1256 NGERE, Université de Lorraine, 54500 Nancy, France.; Service de Neurologie, CHRU de Nancy, 54000 Nancy, France.; Service de Génétique Clinique, CHRU de Nancy, 54000 Nancy, France., Bonnet C; INSERM-U1256 NGERE, Université de Lorraine, 54500 Nancy, France.; Laboratoire de Génétique, CHRU de Nancy, 54000 Nancy, France., Ravenscroft G; Centre for Medical Research University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Western Australia 6009, Australia., Saporta MA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Napierala JS; Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8823, USA., Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, London WC1N 3BG, UK., Deveson IW; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW 2010, Australia.; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Napierala M; Department of Neurology, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8823, USA., Brice A; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Molina Porcel L; Alzheimer's Disease and other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomediques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona, 08036 Barcelona, Spain.; Neurological Tissue Brain Bank, Biobanc-Hospital Clínic-FRCB-IDIBAPS, 08036 Barcelona, Spain., Seilhean D; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Zuchner S; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA., Durr A; Sorbonne Université, Institut du Cerveau - Paris Brain Institute- ICM, Inserm, CNRS, APHP, University Hospital Pitié-Salpêtrière, F-75013 Paris, France., Brais B; Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC H3A 2B4, Canada.; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Oct 08. Date of Electronic Publication: 2024 Oct 08.
DOI:	10.1093/brain/awae312
Abstrakt:	Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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