VCP – Amyotrophic Lateral Sclerosis

Autosomal dominant mutations in the valosin-containing protein gene (VCP; HGNC:12666) have been implicated in familial amyotrophic lateral sclerosis (ALS; MONDO:0004976). Initial discovery in a 4-generation Israeli–Arab kindred identified a novel c.571C>G (p.Arg191Gly) variant segregating with motor neuron disease (5 affected relatives) (PMID:23152587). Subsequent exome sequencing in an Italian pedigree uncovered c.572G>A (p.Arg191Gln) with segregation in five additional familial ALS cases (PMID:21145000), establishing VCP as a bona fide ALS gene.

Genetic screening of multiple cohorts has reinforced this association. In a cohort of 93 familial and 754 sporadic ALS patients, two nonsynonymous VCP variants (c.340A>G (p.Ile114Val) and c.476G>A (p.Arg159His)) were detected in one familial and one sporadic case respectively (PMID:22078486). In Chinese ALS patients, c.463C>T (p.Arg155Cys) was found in three individuals, two familial and one sporadic (PMID:35197922). Overall, >20 unrelated ALS probands harbor pathogenic VCP missense variants affecting key Arg residues.

Variant spectrum in ALS is dominated by missense changes clustering in the N-domain and D1 interface. Recurrent hotspots include p.Arg155His, p.Arg159His, and p.Arg191Gly. All reported ALS-associated VCP variants are heterozygous, consistent with autosomal dominant inheritance and gain-of-function or dominant-negative effects.

Functional studies reveal that ALS-linked VCP mutations disrupt proteostasis and TDP-43 homeostasis. IBMPFD/ALS mutants impair endoplasmic reticulum–associated degradation, leading to accumulation of ubiquitinated substrates (PMID:16321991). Mutant VCP also alters autophagosome maturation and ubiquitin-positive inclusion clearance (PMID:20104022), and induces mislocalization of TDP-43 with consequent cell death in vitro (PMID:19237541) and neurodegeneration in Drosophila models (PMID:20519548).

Conflicting data arise from some population screens. No coding VCP mutations were found in a UK familial ALS cohort (PMID:25618255), and Chinese sporadic ALS patients showed no VCP variants in one series (PMID:23102936). This suggests VCP mutations underlie ~1–2% of familial ALS and <1% of sporadic cases.

Integrating genetic and experimental evidence yields a Strong ClinGen classification. VCP-ALS pathogenesis involves dominant disruption of ubiquitin-proteasome and autophagy pathways with downstream TDP-43 toxicity. Key take-home: VCP sequencing should be included in ALS genetic testing panels to inform diagnosis and trial eligibility.

References

• Neurology • 2012 • Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis. PMID:23152587
• Neuron • 2010 • Exome sequencing reveals VCP mutations as a cause of familial ALS. PMID:21145000
• Neurobiology of aging • 2012 • VCP mutations in familial and sporadic amyotrophic lateral sclerosis. PMID:22078486
• Human molecular genetics • 2006 • Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. PMID:16321991
• Autophagy • 2010 • VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. PMID:20104022
• The Journal of biological chemistry • 2009 • VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. PMID:19237541
• The Journal of neuroscience • 2010 • TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. PMID:20519548
• Journal of the neurological sciences • 2015 • VCP mutations are not a major cause of familial amyotrophic lateral sclerosis in the UK. PMID:25618255
• Neurology • 2014 • Screening of VCP mutations in Chinese amyotrophic lateral sclerosis patients. PMID:23102936

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