Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein

ALSGENS Consortium, FALS Consortium, Project MinE Consortium, CReATe Consortium, Sali M.K. Farhan*, Daniel P. Howrigan, Liam E. Abbott, Joseph R. Klim, Simon D. Topp, Andrea E. Byrnes, Claire Churchhouse, Hemali Phatnani, Bradley N. Smith, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Aleksey Shatunov, Alfredo Iacoangeli, Ahmad Al Khleifat, Daniel A. MordesSulagna Ghosh, Kevin Eggan, Rosa Rademakers, Jacob L. McCauley, Rebecca Schüle, Stephan Züchner, Michael Benatar, J. Paul Taylor, Michael Nalls, Marc Gotkine, Pamela J. Shaw, Karen E. Morrison, Ammar Al-Chalabi, Bryan Traynor, Christopher E. Shaw, David B. Goldstein, Matthew B. Harms, Mark J. Daly, Benjamin M. Neale

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1966-1974
Number of pages9
JournalNature Neuroscience
Issue number12
Early online date25 Nov 2019
Publication statusPublished - 1 Dec 2019


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