The genetic and functional study of the rare variants within oxytocin receptore (OXTR) gene in autism spectrum disorder patients and healthy individuals.

最近对催产素（OT）的研究表明，除了在引产和泌乳中有良好的功能外，这种九氨基酸肽在调节广泛的社会行为（包括伴侣关系，母亲养育和社会记忆）中起着关键作用。在人类遗传学研究中，常见的变异，特别是OXTR的第三内含子中的变异，已被报道与ASD有关。然而，除了常见的变异，罕见的变异还没有被探索。了解OXTR的全面遗传格局，特别是与ASD的关系。对105名日本自闭症谱系障碍（ASD）患者进行了OXTR基因靶向重测序。首次采用长范围PCR扩增OXTR基因的整个区域。对所有患者的PCR产物进行定量，并按等摩尔量合并到4个池中。然后进行下一代测序。最终共鉴定出125个突变，其中26个为新突变，因为它们未在1000基因组计划和其他公共数据库中登记。特别有趣的是，在ASD患者中发现并确认了两个新的非同义snp。生物信息学分析表明，这两个突变体可能具有高度有害的作用，并可能影响受体的激活。在另外384名健康个体中没有发现这两种突变。总之，本项目报道了ASD患者中一些新的OXTR突变。这一发现扩大了我们对罕见的OXTR变异对ASD的贡献的理解。

Recent studies on oxytocin (OT) demonstrate that beyond its well-documented functions in labor induction and milk ejection, this nine-amino-acid peptide plays a critical role in regulating a wide range of social behaviors including pair bonding, maternal parenting and social memory). In human genetic studies, common variants especially the ones in the third intron of OXTR have been reported to be associated with ASD. However besides the common variants, rare variants have been not explored yet.To understand the comprehensive genetic landscape of OXTR especially in relationship to ASD. The targeted re-sequencing of OXTR) was carried out in 105 Japanese autism spectrum disorder (ASD) individuals. First Long range PCR were performed to amplify the whole region of OXTR gene. The PCR products of all patients were quantitated and merged into four pools at equal molar amount. Then Next generation sequencing was followed. Finally a total 125 mutations were identified and 26 were regard as novel mutations since they were not registered in 1000 genome project and other public database. Of particular interest, two novel non-synonymous SNPs were identified and confirmed in ASD patients. Bioinformatics analysis suggest these two mutant may have a highly deleterious role and may affect the receptor activation. And these two mutations were not found in another 384 healthy individuals.In conclusion this project reported a number of novel mutations of OXTR in ASD patients. This finding expands our understanding of the contribution of rare variants of OXTR to ASD.