VCP – Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is a progressive autosomal dominant disorder caused by heterozygous missense mutations in the valosin-containing protein (VCP) gene (HGNC:12666). First described in 2004, VCP mutations disrupt multiple cellular pathways, leading to rimmed vacuolar myopathy, abnormal bone remodeling, and frontotemporal lobar degeneration ([PMID:18845250]).

Genetic evidence includes over 20 unrelated IBMPFD families with more than 150 affected individuals carrying predominantly N-terminal D1 domain missense variants ([PMID:18845250]). The recurrent c.463C>T (p.Arg155Cys) variant has been identified in multiple pedigrees including a Korean family with three affected members ([PMID:21320982]). Additional segregation has been documented in at least 18 affected relatives across Chinese, Japanese, and European families, confirming autosomal dominant inheritance ([PMID:23000505]).

The variant spectrum comprises >10 unique missense changes clustered in the D1–D2 interface, with no reported loss-of-function alleles. The p.Arg155Cys substitution (c.463C>T) serves as a sentinel mutation for clinical testing and genotype-phenotype correlations ([PMID:21320982]).

Functional assays reveal that IBMPFD-associated VCP mutants impair endoplasmic reticulum–associated degradation, leading to accumulation of ubiquitinated substrates and ER stress ([PMID:16321991]). Autophagosome maturation is also disrupted by disease variants such as p.Arg155His, resulting in enlarged ubiquitin-positive autophagic vesicles ([PMID:20104022]).

Neuropathological studies demonstrate mislocalization and aggregation of TDP-43 in nuclei and cytoplasm, linking VCP dysfunction to TDP-43 proteinopathy ([PMID:19237541]). Transgenic and knock-in mouse models expressing the common R155H mutation recapitulate muscle weakness, Paget-like bone lesions, and frontotemporal inclusion pathology, providing concordant in vivo evidence ([PMID:17329348], [PMID:23169451]).

No credible conflicting evidence has emerged to dispute the VCP–IBMPFD association, although VCP mutations may also manifest as multisystem proteinopathy including ALS and Charcot-Marie-Tooth disease.

Given the definitive genetic and functional data, VCP mutation analysis is clinically actionable for diagnosing IBMPFD and guiding early surveillance for Paget disease and cognitive decline. Key Point: Heterozygous VCP missense variants, particularly p.Arg155Cys, are a definitive molecular marker for IBMPFD.

References

• Biochimica et biophysica acta • 2008 • VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. PMID:18845250
• Archives of neurology • 2011 • Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family. PMID:21320982
• 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
• Human molecular genetics • 2007 • Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. PMID:17329348
• Muscle & nerve • 2013 • A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. PMID:23169451

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