期刊
NEUROBIOLOGY OF DISEASE
卷 162, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105578
关键词
MJD; SCA3; Spinocerebellar ataxia; Polyglutamine disease; Age at onset; Genetic modifier
资金
- FEDER -Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 -Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal
- Portuguese funds through FCT -Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior [PTDC/DTP-PIC/2638/2017, POCI-01-0145-FEDER-016592, POCI-01-0145-FEDER-022184]
- ICVS Scientific Microscopy Platform [PPBI-POCI-01-0145-FEDER-022122]
- National funds, through the Foundation for Science and Technology (FCT) [UIDB/50026/2020, UIDP/50026/2020, NORTE-01-0145-FEDER-000013]
- Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)
- FCT [SFRH/BD/147826/2019]
- AFF [SFRH/BD/121101/2016]
- Multiple System Atrophy Trust
- Alzheimer's Research UK
- National Ataxia Foundation
- Fundação para a Ciência e a Tecnologia [SFRH/BD/121101/2016, SFRH/BD/147826/2019] Funding Source: FCT
Machado-Joseph disease (MJD/SCA3), a neurodegenerative disorder, exhibits a wide spectrum of phenotypes. This study identified novel genetic modifiers and disease-modifying pathways contributing to the variable expressivity of MJD. Variants in CFAP57, ACTG1, and DIDO1 were found to consistently modulate the age at onset of MJD in different cohorts. Network analysis highlighted important molecular interactions among the novel MJD modifiers.
Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, sug-gesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuro-muscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE , VCP/ITGB1. We describe novel pathways, modifiers , their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease -modifying targets for MJD and related diseases.
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