Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Brain. 2017 Nov 1;140(11):2860-2878. doi: 10.1093/brain/awx251.

Esther A R Nibbeling ¹, Anna Duarri ¹, Corien C Verschuuren-Bemelmans ¹, Michiel R Fokkens ¹, Juha M Karjalainen ¹, Cleo J L M Smeets ¹, Jelkje J de Boer-Bergsma ¹, Gerben van der Vries ¹, Dennis Dooijes ², Giovana B Bampi ¹, Cleo van Diemen ¹, Ewout Brunt ³, Elly Ippel ², Berry Kremer ³, Monique Vlak ⁴, Noam Adir ⁵, Cisca Wijmenga ¹, Bart P C van de Warrenburg ⁶, Lude Franke ¹, Richard J Sinke ¹, Dineke S Verbeek ¹

Affiliations

1 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
2 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
3 Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
4 Department of Neurology, Medical Center Haaglanden and Bronovo-Nebo, Den Hague, The Netherlands.
5 Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Israel.
6 Department of Neurology, University Medical Center Nijmegen, Nijmegen, The Netherlands.

PMID: 29053796 DOI: 10.1093/brain/awx251

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.

Keywords

genetic network; neurodegeneration; spinocerebellar ataxia; synaptic transmission; whole exome sequencing.

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