@article{0cb40542934f4657b767afcb79a50890,
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 = "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 {ALSGENS Consortium} and Allen, {Andrew S.} and Stanley Appel and Baloh, {Robert H.} and Bedlack, {Richard S.} and Boone, {Braden E.} and Robert Brown and Carulli, {John P.} and Alessandra Chesi and Chung, {Wendy K.} and Cirulli, {Elizabeth T.} and Cooper, {Gregory M.} and Julien Couthouis and Day-Williams, {Aaron G.} and Dion, {Patrick A.} and Summer Gibson and Gitler, {Aaron D.} and Glass, {Jonathan D.} and Yujun Han and Tim Harris and Hayes, {Sebastian D.} and Jones, {Angela L.} and Jonathan Keebler and Krueger, {Brian J.} and Lasseigne, {Brittany N.} and Levy, {Shawn E.} and Yi-Fan Lu and Tom Maniatis and Diane McKenna-Yasek and Miller, {Timothy M.} and Myers, {Richard M.} and Slav{\'e} Petrovski and Pulst, {Stefan M.} and Raphael, {Alya R.} and Ravits, {John M.} and Zhong Ren and Rouleau, {Guy A.} and Sapp, {Peter C.} and Shneider, {Neil A.} and Ericka Simpson and Sims, {Katherine B.} and Staropoli, {John F.} and Waite, {Lindsay L.} and Quanli Wang and Wimbish, {Jack R.} and Xin, {Winnie W.} and {FALS Consortium} and Orla Hardiman and McLaughlin, {Russell L.} and Letizia Mazzini and Blair, {Ian P.} and Williams, {Kelly L.} and Nicholson, {Garth A.} and {Project MinE Consortium} and {CReATe Consortium} 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.}",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41593-019-0530-0",
language = "English",
volume = "22",
pages = "1966--1974",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Springer, Springer Nature",
number = "12",
}