Relevance to Autism

Li et al., 2023 determined that a de novo coding-synonymous variant in the PDHA1 gene originally identified in a Japanese ASD proband in Takata et al., 2018 was a non-canonical splicing variant; subsequent functional analysis by minigene splicing assays demonstrated that this variant resulted in deletion of 23 base pairs from exon 14 of this gene. A frameshift variant in the PDHA1 gene had previously been identified in a female ASD proband from the ASPIRE cohort (Callaghan et al., 2019). An X-chromosome-wide association study of 6,873 individuals with autism from MSSNG, SSC, and SPARK (5,639 males and 1,234 females) and 8,981 controls (3,911 males and 5,070 females) in Mendes et al., 2025 identified an intronic SNP in the PDHA1 gene that reached the significance threshold for association in a both-XWAS analysis; furthermore, rare predicted damaging SNVs (<0.1% frequency in gnomAD) in the PDHA1 gene were found to have a higher frequency in male ASD cases from MSSNG, SSC, and SPARK compared to other family members in this report.

Molecular Function

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome.

External Links

References