@article{4775622b50f84dbb9ffd56ce1c7acc28,
title = "Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein",
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.",
author = "{ALSGENS Consortium} and {FALS Consortium} and {Project MinE Consortium} and {CReATe Consortium} and Farhan, {Sali M.K.} and Howrigan, {Daniel P.} and Abbott, {Liam E.} and Klim, {Joseph R.} and Topp, {Simon D.} and Byrnes, {Andrea E.} and Claire Churchhouse and Hemali Phatnani and Smith, {Bradley N.} and Evadnie Rampersaud and Gang Wu and Joanne Wuu and Aleksey Shatunov and Alfredo Iacoangeli and {Al Khleifat}, Ahmad and Mordes, {Daniel A.} and Sulagna Ghosh and Kevin Eggan and Rosa Rademakers and McCauley, {Jacob L.} and Rebecca Sch{\"u}le and Stephan Z{\"u}chner and Michael Benatar and Taylor, {J. Paul} and Michael Nalls and Marc Gotkine and Shaw, {Pamela J.} and Morrison, {Karen E.} and Ammar Al-Chalabi and Bryan Traynor and Shaw, {Christopher E.} and Goldstein, {David B.} and Harms, {Matthew B.} and Daly, {Mark J.} and Neale, {Benjamin M.}",
note = "Funding Information: This consortium is funded through collaboration between NCATS and the NINDS. Additional support is provided by the ALS Association (17-LGCA-331). S.M.K.F. was supported by the ALS Canada Tim E. No{\"e}l Postdoctoral Fellowship. J.R.K. was supported by the Project ALS Tom Kirchhoff Family Postdoctoral Fellowship and acknowledges K. Mamia and L. T. Kane for their work banking fibroblasts. Funding Information: The authors thank and acknowledge the consent and cooperation of all study participants. Many thanks are given to F. Cerrato for helping assemble the dataset and providing general project management, and to T. Poterba, J. Bloom, D. King and C. Seed for their assistance in Hail. Data used in this research were in part obtained from the UK MND Collections for MND Research, funded by the MND Association and the Wellcome Trust. The authors thank people from MND and their families for their participation in this project. The project is supported through the following funding organizations under the aegis of the JPND (www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1)), the Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. Samples used in this research were in part obtained from the UK National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. The CReATe consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41593-019-0530-0",
language = "English (US)",
volume = "22",
pages = "1966--1974",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "12",
}