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, which was 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 an ALS patient carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat shock protein family (HSP40), which along with HSP70 proteins, facilitate 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 leading to protein aggregation, a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

“…DNAJB5 was recently identified as a candidate gene for hereditary myoclonus and progressive distal muscular atrophy [37], but its pathogenic role awaits confirmation. DNAJC7, on the other hand, is emerging as a candidate gene for amyotrophic lateral sclerosis (ALS) [38].…”

Rapid progressive ALS in a patient with a DNAJC7 loss-of-function mutation

“…In another recent study, DNAJC7 protein-truncating variants were identified in 8 out of 5,095 (0.16%) ALS patients. 1 These findings suggest that DNAJC7 mutations are not a common cause of ALS.…”

“…Similar DNAJC7 LOF mutation, p.R156*, has been demonstrated with significantly reduced protein production in vitro. 1 The DNAJC7 p.Q134Rfs*6 mutation was identified in one of the 254 unexplained sporadic ALS patients (0.4%). In another recent study, DNAJC7 protein-truncating variants were identified in 8 out of 5,095 (0.16%) ALS patients.…”

A Knowledge-Based Machine Learning Approach to Gene Prioritisation in Amyotrophic Lateral Sclerosis

“…The genetics of ALS has proven challenging, and even though great progress has been made by generating and analysing large multi-omics datasets [36,[62][63][64][65][66][67][68][69][70][71], the causes of ALS in most patients (~85%) remain unexplained. Using machine learning models to leverage our current knowledge of ALS and other diseases could allow us to accelerate our progress in the understanding of the genetic causes of ALS and lead towards new avenues of treatment.…”