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

自闭症谱系障碍患者和健康个体中催产素受体 (OXTR) 基因内罕见变异的遗传和功能研究。

• 批准号: 25893290
• 负责人: LIU XIAOXI
• 金额: $ 1.75万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2013
• 资助国家: 日本
• 起止时间: 2013-08-30 至 2015-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-25893290/
• 关键词: Autism spectrum disorder; Oxytocin receptor; OXTR; ASD

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.

最近对催产素(OT)的研究表明，除了在引产和排乳中的已知功能外，这种由九个氨基酸组成的多肽还在调节一系列社会行为方面发挥关键作用，包括配对纽带、母亲养育和社会记忆。在人类遗传学研究中，常见的变异，特别是OXTR第三内含子中的变异，已被报道与ASD有关。然而，除了常见的变异外，还没有发现罕见的变异。了解OXTR的全面遗传图景，特别是与ASD的关系。对105例日本自闭症谱系障碍(ASD)患者进行了OXTR靶向重测序。首先用长程聚合酶链式反应扩增OXTR基因全长片段。所有患者的聚合酶链式反应产物被定量并合并到四个等摩尔量的池中。然后进行下一代测序。最终，共鉴定出125个突变，其中26个未在1000基因组计划和其他公共数据库中登记，被认为是新的突变。特别有趣的是，在ASD患者中发现并确认了两个新的非同义SNPs。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。综上所述，本项目报告了ASD患者中OXTR的一些新突变。这一发现扩大了我们对OXTR罕见变异在ASD发病中的作用的理解。