Relevance to Autism

An X-chromosome-wide association (XWAS) 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., 2024 identified three intronic SNPs in the HTR2C gene that reached the significance threshold for association in an XWAS meta-analysis; two of these SNPs also reached the significance threshold for association (P < 1.07E-05) in a sex-stratified female-XWAS analysis. Furthermore, rare predicted damaging SNVs (<0.1% frequency in gnomAD) in the HTR2C gene were found to have a higher frequency in ASD cases (males, females, and both sexes combined) from MSSNG, SSC, and SPARK compared to other family members. Sejourne et al., 2015 had previously found that adult Htr2c knockout mice exhibited social behavior deficits that coincided with the onset of seizure susceptibility.

Molecular Function

This gene encodes a seven-transmembrane G-protein-coupled receptor. The encoded protein responds to signaling through the neurotransmitter serotonin. The mRNA of this gene is subject to multiple RNA editing events, where adenosine residues encoded by the genome are converted to inosines. RNA editing is predicted to alter the structure of the second intracellular loop, thereby generating alternate protein forms with decreased ability to interact with G proteins. Abnormalities in RNA editing of this gene have been detected in victims of suicide that suffer from depression. In addition, naturally-occuring variation in the promoter and 5' non-coding and coding regions of this gene may show statistically-significant association with mental illness and behavioral disorders.

External Links

References