Genotype-phenotype study in patients with VCP valosin-containing protein mutations associated with multisystem proteinopathy

Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males, 113 females) from 36 families carrying 15 different VCP mutations. We analyzed correlation between the different mutations and prevalence, age of onset and severity of myopathy, PDB, and FTD, and other comorbidities. Myopathy, PDB and FTD was present in 90%, 42% and 30% of the patients respectively, beginning at an average age of 43 years, 41 years, and 56 years respectively. Approximately 9% of patients with VCP mutations had an ALS phenotype, 4% had been diagnosed with Parkinson’s disease (PD), and 2% had been diagnosed with Alzheimer’s disease (AD). Large inter and intra-familial variation made establishing correlations difficult. We did not find a correlation between the mutation type and the incidence of any of the clinical features associated with VCP disease, except for the absence of PDB with the R159C mutation in our cohort and R159C having a later age of onset of myopathy compared to other molecular subtypes. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy, Paget disease of bone, frontotemporal dementia, amyotropic lateral sclerosis and Parkinson’s disease. We studied the largest group of individuals (total 231: 118 males, 113 females) from 36 families carrying 15 different VCP mutations to establish genotype-phenotype correlation. Large intra-familial and interfamilial variations made establishing correlations difficult to establish except for later age of onset with R159C mutations.