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
An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP
DD, ID
ASD or autistic features, ADHD, epilepsy/seizures,
Rescue Type:
RESCUE-Dietary
Rescue Paradigm:
Mice were provided with leucine-supplemented water (1.8%) for 7 days prior to testing and then continuously for the duration of the entire behavioral task. Leucine solutions were replaced daily throughout the entire assay period. Leucine uptake was estimated to be 1.8g leucine/100 mL x 5 mL water/25 g body weight = 3.6 mg/g mouse body weight/day.
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Description: Vcp mutant mice fed 19% protein chow and treated with leucine exhibited a slight decrease in total distance traveled compared to untreated mutant mice.
Description: Vcp mutant mice fed 19% protein chow and treated with leucine exhibited increased dendritic spine density to a level comparable to wildtype controls.
Description: Vcp mutant mice fed 19% protein chow and treated with leucine exhibited an increase in time spent interacting with stranger mice, to a level comparable to that of wildtype controls.
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.
