DNAJC7 – DNAJC7-related Amyotrophic Lateral Sclerosis

DNAJC7 encodes a member of the HSP40 family involved in protein homeostasis. A landmark exome study of 3,864 ALS cases and 7,839 controls demonstrated a significant excess of rare protein-truncating variants in DNAJC7 compared to controls ([PMID:31768050]). This genome-wide significant signal highlights DNAJC7 as a novel ALS risk gene, independent of established loci such as SOD1, NEK1, and FUS.

Genetic evidence includes multiple distinct truncating and missense variants in unrelated ALS patients. Representative among these is c.466C>T (p.Arg156Ter), which recurs in independent cohorts and reached genome-wide significance in case–control burden analyses ([PMID:31768050]). Other pathogenic candidates, such as c.712A>G (p.Arg238Gly), were identified in sporadic patients from Mainland China ([PMID:33193563]).

Replication efforts in Chinese cohorts uncovered rare DNAJC7 variants in 1/578 patients ([PMID:33193563]) and additional missense alleles with uncertain significance in larger screens ([PMID:32897108], [PMID:34233860]). Although burden analyses in these populations did not show enrichment, these studies expand the variant spectrum and suggest population-specific frequencies.

Functional assays support a haploinsufficiency mechanism. Immunoblotting of patient-derived fibroblasts carrying p.Arg156Ter revealed marked depletion of DNAJC7 protein, consistent with loss of function and downstream protein aggregation ([PMID:31768050]). This mirrors the pathological hallmark of misfolded protein accumulation in ALS.

Integration of genetic and functional data yields a Moderate clinical validity classification. While the original exome association and cellular assays provide robust support, limited segregation data and variable replication temper definitive assignment. Additional large cohorts and family studies could strengthen the evidence cap.

Key Take-home: Rare heterozygous loss-of-function variants in DNAJC7 confer increased risk for autosomal dominant ALS, with functional assays confirming protein depletion and a likely haploinsufficient mechanism—informing genetic diagnosis and future therapeutic strategies.

References

• Nature neuroscience • 2019 • Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein. PMID:31768050
• Frontiers in genetics • 2020 • A Novel Potentially Pathogenic Rare Variant in the DNAJC7 Gene Identified in Amyotrophic Lateral Sclerosis Patients From Mainland China. PMID:33193563
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2021 • Mutations of DNAJC7 are rare in Chinese amyotrophic lateral sclerosis patients. PMID:32897108
• Neurobiology of aging • 2021 • Validation of the pathogenic role of rare DNAJC7 variants in Chinese patients with amyotrophic lateral sclerosis. PMID:34233860

Evidence Based Scoring (AI generated)