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
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
DD, ID
ASD or autistic features, ADHD, epilepsy/seizures,
The Vcp gene encodes for Valosin-containing protein, and it is associated with multiple neurological disorders. The R95G knockin model exhibits autism-like behaviors, including social deficits and motor phenotypes. The phenotypes resulting from the same mutation are modulated by the protein levels in the diet. Supplementing the diet with leucine improves some of the behavioral phenotypes.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A recombineering-based method was used to generate knockin mutant mice. A genomic fragment covering from intron 1 to intron 4 of the Vcp gene was subcloned from bacterial artificial chromosome clone RP23-343E15 into a modified pBluescript vector. The R95G point mutation at the third exon and an EcoRV site in the third intron were generated by direct mutagenesis. The targeting vector was electroporated into C57BL/6 embryonic stem cells for production of chimeric mice. Animals accessed water ad libitum and food comprised of chow 5K54, which contains 19% protein.
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A recombineering-based method was used to generate knockin mutant mice. A genomic fragment covering from intron 1 to intron 4 of the Vcp gene was subcloned from bacterial artificial chromosome clone RP23-343E15 into a modified pBluescript vector. The R95G point mutation at the third exon and an EcoRV site in the third intron were generated by direct mutagenesis. The targeting vector was electroporated into C57BL/6 embryonic stem cells for production of chimeric mice. Animals accessed water ad libitum and food comprised of chow 5010, which contains 24.6% protein.
Allele Type: Knockin
Strain of Origin: C57BL/6
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Vcp mutant mice fed 19% protein chow spent significantly less time interacting with stranger 1, as demonstrated by the preference index, compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s1), object in chamber 2
Description: Vcp mutant mice fed 19% protein chow exhibited reduced ultrasonic vocalization production compared to wildtype mice, though only the results at P8 were statistically significant.
Description: Vcp mutant mice fed 24.6% protein chow exhibited a significant decrease in the amount of time spent interacting with a stranger mouse over a familiar mouse, as demonstrated by a decrease in the preference index, compared to wildtype controls.
Exp Paradigm: stranger mouse in chamber 1 (s3), familiar mouse in chamber 2 (s1), 24 hours after phase 2 of testing
Description: Vcp mutant mice fed 24.6% protein chow exhibited a significant decrease in freezing responses on day 6, with approximately 20% of time spent freezing compared to over 40% in wildtype controls.
Exp Paradigm: single foot shock applied daily on training days 1â??5; contextual memory in the absence of foot shock measured on day 6
