Somatic instability of the <i>FGF14</i> -SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum

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.

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Journal
Brain
Published
2024-10-07
DOI
https://doi.org/10.1093/brain/awae312
Citations
9
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
Field-Weighted Citation Impact
2.41

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article

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

Susana Boluda, Jillian M. Hammond, Laura Molina‐Porcel, Viorica Chelban et al.
9 citations
Brain
Genetic Neurodegenerative Diseases
2.41
article

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

Susana Boluda, Jillian M. Hammond, Laura Molina‐Porcel, Viorica Chelban, Marie-Josée Dicaire, M. Renaud, Kevin Petrecca, Mario Saporta, Schahram Akbarian, Alexandra Dürr, Alexis Brice, Maryam Safisamghabadi, Bernard Brais, Stephan Züchner, Jean‐Loup Méreaux, Matt C. Danzi, Danielle Seilhean, David Pellerin, Catherine Ashton, Karen Usdin, Jill S. Napierala, Céline Bonnet, Christopher Yanick, Марек Напиерала, Zane Jaunmuktane, Sathiji Nageshwaran, Gianina Ravenscroft, Ira W. Deveson, Henry Houlden, Gabriel E. Matos-Rodrigues, Guinevere Spurdens, Brandon J. Gerhart, Hamin Lee, Claire-Sophie Davoine, Phuong Uyen Le, André Nussenzweig, David Genı́s
article en
9 citations

Abstract

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.

BrainVol. 148(4)
Montreal Neurological Institute and Hospital (CA), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Allen Institute for Brain Science (US), Garvan Institute of Medical Research (AU), University of Miami (US), Inserm (FR), University of California, Los Angeles (US), The University of Western Australia (AU), Royal Perth Hospital (AU), Harry Perkins Institute of Medical Research (AU), UNSW Sydney (AU), Sorbonne Université (FR), National Institute of Diabetes and Digestive and Kidney Diseases (US), Centre Hospitalier Régional et Universitaire de Nancy (FR), Institut d'Investigació Biomèdica de Girona (ES), Hospital Santa Caterina (ES), Nicolae Testemițanu State University of Medicine and Pharmacy (MD), Dr. John T. Macdonald Foundation (US), National Cancer Institute (US), Murdoch Children's Research Institute (AU), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), Fundació Clínic per a la Recerca Biomèdica (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Nutrition-Génétique et Exposition aux Risques Environnementaux (FR), University College London (GB), McGill University (CA), Universitat de Barcelona (ES), The University of Texas Southwestern Medical Center (US), Université de Lorraine (FR), Icahn School of Medicine at Mount Sinai (US)
Michael J. Fox Foundation for Parkinson's Research, Friedreich's Ataxia Research Alliance, Wellcome Trust, Multiple System Atrophy Trust, Multiple System Atrophy Coalition, National Institute for Health and Care Research, Ataxia UK, Guarantors of Brain, Rosetrees Trust, Alzheimer’s Research UK, Fondation pour la Recherche Médicale, Koning Boudewijnstichting, University College London Hospitals NHS Foundation Trust, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, UCLH Biomedical Research Centre, University College London Hospitals Biomedical Research Centre, National Institute on Drug Abuse, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 11%
Genetic Neurodegenerative Diseases
2.41
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