Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case-control study in a Japanese population and functional analysis

作者：Ma Wen Jie; Hashii Minako; Munesue Toshio; Hayashi Kenshi; Yagi Kunimasa; Yamagishi Masakazu; Higashida Haruhiro; Yokoyama Shigeru^*

来源：Molecular Autism, 2013, 4: 22.

DOI：10.1186/2040-2392-4-22

• Autism spectrum disorders
• Inositol-1,4,5-trisphosphate
• Intracellular free calcium
• Oxytocin
• Oxytocin receptor
• Single-nucleotide variation

Background: The human oxytocin receptor (hOXTR) is implicated in the etiology of autism spectrum disorders (ASDs) and is a potential target for therapeutic intervention. Several studies have reported single-nucleotide polymorphisms (SNPs) of the OXTR gene associated with ASDs. These SNPs, however, reside outside the protein-coding region. Not much is known about genetic variations that cause amino acid substitutions that alter receptor functions. %26lt;br%26gt;Methods: Variations in the OXTR gene were analyzed in 132 ASD patients at Kanazawa University Hospital in Japan and 248 unrelated healthy Japanese volunteers by re-sequencing and real-time polymerase chain reaction-based genotyping. Functional changes in variant OXTRs were assessed by radioligand binding assay and measurements of intracellular free calcium concentrations ([Ca2+](i)) and inositol 1,4,5-trisphosphate (IP3) levels. %26lt;br%26gt;Results: Six subjects (4.5%) in the ASD group and two in the control group (0.8%) were identified as heterozygotes carrying the R376G variation (rs35062132; c.1126C%26gt;G); one individual from the ASD group (0.8%) and three members of the control group (1.2%) were found to be carrying R376C (c.1126C%26gt;T). The C/G genotype significantly correlated with an increased risk of ASDs (odds ratio (OR) = 5.83; 95% confidence interval (CI) = 1.16 to 29.33; P = 0.024, Fisher%26apos;s exact test). Consistently, the G allele showed a correlation with an increased likelihood of ASDs (OR = 5.73; 95% CI = 1.15 to 28.61; P = 0.024, Fisher%26apos;s exact test). The frequencies of the C/T genotype and the T allele in the ASD and control groups did not differ significantly. We also examined changes in agonist-induced cellular responses mediated by the variant receptors hOXTR-376G and hOXTR-376C. OXT-induced receptor internalization and recycling were faster in hOXTR-376G-expressing HEK-293 cells than in cells expressing hOXTR-376R or hOXTR-376C. In addition, the elevation in [Ca2+](i) and IP3 formation decreased in the cells expressing hOXTR-376G and hOXTR-376C tagged with enhanced green fluorescent protein (EGFP), in comparison with the cells expressing the common-type hOXTR-376R tagged with EGFP. %26lt;br%26gt;Conclusions: These results suggest that the rare genetic variation rs35062132 might contribute to the pathogenesis of ASDs, and could provide a molecular basis of individual differences in OXTR-mediated modulation of social behavior.

• 出版日期2013-7-1