CHCHD10 – Amyotrophic Lateral Sclerosis

Dominant CHCHD10 variants have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS) patients. Autosomal dominant inheritance has been observed with segregating p.Ser59Leu in a large kindred manifesting motor neuron degeneration and frontotemporal dementia (3 affected) (PMID:25155093). Additional rare missense and nonsense variants (p.Pro34Ser, p.Ala35Asp, p.Arg15Leu, p.Gly66Val) have been reported in ~10 unrelated ALS probands across European and Asian cohorts (≤1% frequency) (PMID:25726362, PMID:27056076, PMID:28069311, PMID:28318595). A large burden study found no enrichment of CHCHD10 missense variants in 4,365 ALS versus 1,832 controls (PMID:30014597).

Robust functional data support a dominant gain-of-function mechanism. p.Ser59Leu knock-in mice develop mitochondrial cardiomyopathy and neuromuscular junction degeneration with motor neuron loss (PMID:30874923), and p.Pro80Leu zebrafish display motor impairment and NMJ defects (PMID:39260590). CHCHD10 Q108P disrupts Mia40-mediated mitochondrial import (PMID:29789341), and loss-of-function mutations induce cytoplasmic TDP-43 aggregates and synaptic damage (PMID:28585542). CHCHD10 mutants also impair PARL-PINK1–dependent mitophagy, promoting TDP-43 pathology (PMID:38132101). Together, genetic and experimental evidence support a role for CHCHD10 variants in ALS, although rare frequency and lack of burden enrichment temper diagnostic sensitivity.

Key take-home: CHCHD10 should be considered in dominant ALS, especially with early mitochondrial dysfunction or FTD features.

References

• Neurobiology of aging • 2014 • Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. PMID:25155093
• Neurobiology of aging • 2015 • CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. PMID:25726362
• Molecular neurobiology • 2017 • Mutation Screening of the CHCHD10 Gene in Chinese Patients with Amyotrophic Lateral Sclerosis. PMID:27056076
• Neurobiology of aging • 2017 • Investigating the role of ALS genes CHCHD10 and TUBA4A in Belgian FTD-ALS spectrum patients. PMID:28069311
• Neurobiology of aging • 2017 • CHCHD10 mutations in patients with amyotrophic lateral sclerosis in Mainland China. PMID:28318595
• Annals of neurology • 2018 • CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence? PMID:30014597
• Acta neuropathologica • 2019 • Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10S59L/+ mouse. PMID:30874923
• Experimental neurology • 2024 • CHCHD10P80L knock-in zebrafish display a mild ALS-like phenotype. PMID:39260590
• EMBO molecular medicine • 2018 • A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS. PMID:29789341
• Nature communications • 2017 • Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. PMID:28585542
• Cells • 2023 • Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion. PMID:38132101

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