VCP – Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia Type 1

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (IBMPFD1) is a rare adult-onset multisystem proteinopathy characterized by progressive myopathy (HP:0003198), osteolytic bone lesions, and frontotemporal dementia (HP:0002145). Heterozygous variants in the VCP gene underlie this autosomal dominant condition, historically termed multisystem proteinopathy 1 or IBMPFD (PMID:36980948; PMID:35841038).

Genetic evidence includes five patients, three from a single pedigree, harboring novel VCP missense variants: c.760A>T (p.Ile254Phe), c.478G>A (p.Ala160Thr), and c.1106T>C (p.Ile369Thr) (PMID:36980948). A retrospective survey of 106 unrelated families confirmed segregation of monoallelic VCP variants with disease features across multiple generations (PMID:35841038). These data, combined with consistent autosomal dominant transmission and co-segregation in three affected relatives, support a definitive gene–disease relationship.

The pathogenic variant spectrum is dominated by missense substitutions clustering at the N-D1 interface. Recurrent alleles such as c.464G>A (p.Arg155His) have been identified in multiple cohorts, alongside rarer substitutions including c.283C>G (p.Arg95Gly), c.271A>T (p.Asn91Tyr), and c.553G>A (p.Glu185Lys), illustrating locus heterogeneity.

Functional studies demonstrate a gain-of-function mechanism. Disease-associated VCP mutations impair endoplasmic reticulum–associated degradation, leading to accumulation of ubiquitinated substrates and disrupted ER-associated degradation (PMID:16321991). Mutant VCP also blocks autophagosome maturation, causing accumulation of immature ubiquitin-positive autophagic vesicles (PMID:20104022). In vivo, VCPR155H/+ knock-in mice recapitulate muscle weakness, TDP-43 pathology, and Paget-like bone lesions (PMID:23169451), and neuronal overexpression of VCPA232E induces ubiquitin and TDP-43 inclusions with cognitive deficits (PMID:23747512).

Although VCP overactivity has been linked to malignancy, epidemiologic data did not reveal an increased rate of common cancers compared to the general population, suggesting that elevated cancer incidence in IBMPFD1 may reflect early mortality rather than variant-specific oncogenesis (PMID:35841038).

Collectively, these genetic and experimental data reach a Definitive ClinGen classification for VCP in IBMPFD1. Genetic testing for VCP should be integrated into the diagnostic workup of adult-onset myopathy, Paget disease of bone, or frontotemporal dementia to enable early management and family counseling.

References

• Genes • 2023 • Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1. PMID:36980948
• Orphanet Journal of Rare Diseases • 2022 • A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy. PMID:35841038
• 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
• Muscle & Nerve • 2013 • A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. PMID:23169451
• The American Journal of Pathology • 2013 • Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice. PMID:23747512

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