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- Title
Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.
- Authors
Nibbeling, Esther A. R.; Duarri, Anna; Verschuuren-Bemelmans, Corien C.; Fokkens, Michiel R.; Karjalainen, Juha M.; Smeets, Cleo J. L. M.; de Boer-Bergsma, Jelkje J.; van der Vries, Gerben; Dooijes, Dennis; Bampi, Giovana B.; Diemen, Cleo van; Brunt, Ewout; Ippel, Elly; Kremer, Berry; Vlak, Monique; Adir, Noam; Wijmenga, Cisca; van de Warrenburg, Bart P. C.; Franke, Lude; Sinke, Richard J.
- Abstract
The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.
- Subjects
SPINOCEREBELLAR ataxia; GENETIC nomenclature; NUCLEOTIDE sequencing; NEURAL transmission; NEURODEGENERATION
- Publication
Brain: A Journal of Neurology, 2017, Vol 140, Issue 11, p2860
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awx251