Relevance to Autism

Mah-som et al., 2023 identified 13 unrelated individuals harboring heterozygous variants in the VCP gene associated with a childhood-onset order characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly; three of the individuals in this study were formally diagnosed with autism (one of whom was enrolled in the SPARK study), while several additional individuals presented with autistic features and/or motor stereotypy. Furthermore, all disease-associated VCP missense and in-frame deletion variants reported in Mah-som et al., 2023 were experimentally shown to cause either a statistically significant increase or decrease in ATPase function compared to wild-type VCP, consistent with a gain-of-function or loss-of-function effect, respectively. A de novo loss-of-function variant and additional de novo missense variants in the VCP gene had previously been reported in ASD probands from the Simons Simplex Collection, the SPARK cohort, and the Autism Simplex Collection (O'Roak et al., 2014; Trost et al., 2022). Huang et al., 2020 observed that knock-in mice with a p.Arg95Gly mutation, which was originally identiifed in patients with IBMPFD and had been found to reduce the protein synthesis efficiency of neurons, displayed social deficits and reduced vocal communications.

Molecular Function

This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients.

External Links

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