VDAC3 – Autism Spectrum Disorder

In a recent study, two affected siblings from a Sardinian multiplex family with autism spectrum disorder (ASD) were reported to harbor a rare frameshift mutation in VDAC3 (PMID:30736458). Although the cohort is limited to a single family, this observation raises the possibility that VDAC3 dysfunction contributes to ASD susceptibility. The clinical genetic evidence is thus classified as limited due to the small number of probands and the absence of extensive segregation data.

The genetic evidence is further underscored by the identification of a rare variant, c.772_790del (p.Ser258TrpfsTer39), in VDAC3. This variant is predicted to result in loss-of-function, aligning with the gene’s intolerance to disruptive mutations. While the exact mode of inheritance is not definitively established, the heterozygous presentation in affected individuals is most compatible with an autosomal dominant pattern. However, no additional affected relatives with the variant were reported in this study.

Functional studies have provided important insights into VDAC3 biology. Research in muscle tissues indicates that VDAC3 plays a role in modulating mitochondrial respiratory activity in a tissue-specific manner (PMID:20875390). Furthermore, an investigation of an alternatively spliced isoform of VDAC3 revealed changes in channel function that could influence cellular metabolism (PMID:9804816). Additional work using electrophysiological and biochemical assays supports differences in channel gating and redox sensitivity relative to other VDAC isoforms (PMID:35082690), suggesting functional mechanisms that may underlie neurodevelopmental disturbances.

Despite these converging lines of evidence, some studies have not directly linked VDAC3 to neurodevelopmental phenotypes. Variability in experimental outcomes and the limited number of clinical reports underscore the need for further research to firmly establish the gene’s role in ASD. Nonetheless, the combined genetic and functional data provide a rationale for continued investigation of VDAC3 in the context of autism.

In summary, while the evidence linking VDAC3 to ASD is currently limited, the identification of a rare frameshift variant together with supportive functional studies lends preliminary support to its role in the disorder. This association, if corroborated by future research, may offer novel diagnostic insights and inform personalized therapeutic strategies for ASD.

Key Take‑home: The observed rare loss‑of‑function variant in VDAC3, combined with functional data demonstrating tissue‐specific mitochondrial dysfunction, highlights its potential diagnostic and research value in autism spectrum disorder.

References

• Journal of clinical medicine • 2019 • Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post‑Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene PMID:30736458
• Biochimica et biophysica acta • 2011 • VDAC3 has differing mitochondrial functions in two types of striated muscles PMID:20875390
• The Journal of biological chemistry • 1998 • A novel isoform of the mitochondrial outer membrane protein VDAC3 via alternative splicing of a 3‑base exon. Functional characteristics and subcellular localization PMID:9804816
• Frontiers in physiology • 2021 • Voltage‑Dependent Anion Selective Channel 3: Unraveling Structural and Functional Features of the Least Known Porin Isoform PMID:35082690

Evidence Based Scoring (AI generated)