Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

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

doi:10.1093/brain/awx251

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

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

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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.

Original language	English
Pages (from-to)	2860-2878
Number of pages	19
Journal	Brain
Volume	140
Issue number	11
DOIs	https://doi.org/10.1093/brain/awx251
Publication status	Published - 1-Nov-2017

Keywords

spinocerebellar ataxia
whole exome sequencing
synaptic transmission
neurodegeneration
genetic network
DOMINANT CEREBELLAR ATAXIAS
MISSENSE MUTATIONS
POLYGLUTAMINE EXPANSIONS
PROTOCADHERIN FAT1
MOTOR DYSFUNCTION
CALCIUM-CHANNEL
EPISODIC ATAXIA
ALPHA-SYNUCLEIN
ACTIN DYNAMICS
HUMAN CANCERS

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Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxiaFinal publisher's version, 1.31 MBLicence: Taverne

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Nibbeling, E. A. R., Duarri, A., Verschuuren-Bemelmans, C. C., Fokkens, M. R., Karjalainen, J. M., Smeets, C. J. L. M., de Boer-Bergsma, J. J., van der Vries, G., Dooijes, D., Bampi, G. B., van Diemen, C., Brunt, E., Ippel, E., Kremer, B., Vlak, M., Adir, N., Wijmenga, C., Warrenburg, B. P. C. V. D., Franke, L., ... Verbeek, D. S. (2017). Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain, 140(11), 2860-2878. https://doi.org/10.1093/brain/awx251

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title = "Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia",

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 = "spinocerebellar ataxia, whole exome sequencing, synaptic transmission, neurodegeneration, genetic network, DOMINANT CEREBELLAR ATAXIAS, MISSENSE MUTATIONS, POLYGLUTAMINE EXPANSIONS, PROTOCADHERIN FAT1, MOTOR DYSFUNCTION, CALCIUM-CHANNEL, EPISODIC ATAXIA, ALPHA-SYNUCLEIN, ACTIN DYNAMICS, HUMAN CANCERS",

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

year = "2017",

month = nov,

day = "1",

doi = "10.1093/brain/awx251",

language = "English",

volume = "140",

pages = "2860--2878",

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Nibbeling, EAR, Duarri, A, Verschuuren-Bemelmans, CC, Fokkens, MR, Karjalainen, JM, Smeets, CJLM, de Boer-Bergsma, JJ, van der Vries, G, Dooijes, D, Bampi, GB, van Diemen, C, Brunt, E, Ippel, E, Kremer, B, Vlak, M, Adir, N, Wijmenga, C, Warrenburg, BPCVD, Franke, L, Sinke, RJ & Verbeek, DS 2017, 'Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia', Brain, vol. 140, no. 11, pp. 2860-2878. https://doi.org/10.1093/brain/awx251

TY - JOUR

T1 - Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

AU - Nibbeling, Esther A R

AU - Duarri, Anna

AU - Verschuuren-Bemelmans, Corien C

AU - Fokkens, Michiel R

AU - Karjalainen, Juha M

AU - Smeets, Cleo J L M

AU - de Boer-Bergsma, Jelkje J

AU - van der Vries, Gerben

AU - Dooijes, Dennis

AU - Bampi, Giovana B

AU - van Diemen, Cleo

AU - Brunt, Ewout

AU - Ippel, Elly

AU - Kremer, Berry

AU - Vlak, Monique

AU - Adir, Noam

AU - Wijmenga, Cisca

AU - Warrenburg, Bart P C van de

AU - Franke, Lude

AU - Sinke, Richard J

AU - Verbeek, Dineke S

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - spinocerebellar ataxia

KW - whole exome sequencing

KW - synaptic transmission

KW - neurodegeneration

KW - genetic network

KW - DOMINANT CEREBELLAR ATAXIAS

KW - MISSENSE MUTATIONS

KW - POLYGLUTAMINE EXPANSIONS

KW - PROTOCADHERIN FAT1

KW - MOTOR DYSFUNCTION

KW - CALCIUM-CHANNEL

KW - EPISODIC ATAXIA

KW - ALPHA-SYNUCLEIN

KW - ACTIN DYNAMICS

KW - HUMAN CANCERS

U2 - 10.1093/brain/awx251

DO - 10.1093/brain/awx251

M3 - Article

C2 - 29053796

SN - 0006-8950

VL - 140

SP - 2860

EP - 2878

JO - Brain

JF - Brain

IS - 11

ER -

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Abstract

Keywords

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