| Literature DB >> 31768050 |
Sali M K Farhan1,2,3, Daniel P Howrigan4,5,6, Liam E Abbott4,5,6, Joseph R Klim7, Simon D Topp8, Andrea E Byrnes4,5,6, Claire Churchhouse4,5,6, Hemali Phatnani9, Bradley N Smith8, Evadnie Rampersaud10, Gang Wu10, Joanne Wuu11, Aleksey Shatunov12, Alfredo Iacoangeli12,13, Ahmad Al Khleifat12, Daniel A Mordes7, Sulagna Ghosh6,7, Kevin Eggan6,7, Rosa Rademakers14, Jacob L McCauley15,16, Rebecca Schüle17, Stephan Züchner15,16, Michael Benatar11, J Paul Taylor18,19, Michael Nalls20,21, Marc Gotkine22, Pamela J Shaw23, Karen E Morrison24, Ammar Al-Chalabi12,25, Bryan Traynor20,26, Christopher E Shaw8,27, David B Goldstein28, Matthew B Harms29, Mark J Daly4,5,6, Benjamin M Neale30,31,32.
Abstract
To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.Entities:
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Year: 2019 PMID： 31768050 PMCID： PMC6919277 DOI： 10.1038/s41593-019-0530-0
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 28.771