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.
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.
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DOI：
10.1186/2040-2392-4-22
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发表时间：
2013-07-01
期刊：
影响因子：
6.2
通讯作者：
Yokoyama S
中科院分区：
文献类型：
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作者：
Ma WJ;Hashii M;Munesue T;Hayashi K;Yagi K;Yamagishi M;Higashida H;Yokoyama S
人类催产素受体（hOXTR）与自闭症谱系障碍（ASD）的病因学有关，是治疗干预的潜在靶点。多项研究报告了与自闭症谱系障碍相关的OXTR基因单核苷酸多态性（SNP）。然而，这些SNP位于蛋白质编码区之外。对于引起氨基酸替换从而改变受体功能的遗传变异，我们知之甚少。通过重新测序和基于实时聚合酶链反应的基因分型，分析了日本金泽大学医院的132名ASD患者和248名无关的健康日本志愿者的OXTR基因变异。通过放射性配体结合测定和细胞内游离钙浓度（[Ca 2 +]i）和1，4，5-三磷酸肌醇（IP 3）水平的测量来评估变体OXTR的功能变化。ASD组的6名受试者（4.5%）和对照组的2名受试者（0.8%）被鉴定为携带R376 G变异（rs35062132; c.1126C>G）的杂合子; ASD组的1名个体（0.8%）和对照组的3名成员（1.2%）被发现携带R376 C（c.1126C>T）。C/G基因型与ASD风险增加显著相关（比值比（OR）= 5.83; 95%置信区间（CI）= 1.16至29.33; P = 0.024，Fisher精确检验）。G等位基因与ASD的发生相关（OR = 5.73; 95%CI = 1.15 ~ 28.61; P = 0.024，Fisher精确检验）。ASD组和对照组C/T基因型和T等位基因频率无显著差异。我们还检查了由变体受体hOXTR-376 G和hOXTR-376 C介导的激动剂诱导的细胞应答的变化。在表达hOXTR-376 G的HEK-293细胞中，OXT诱导的受体内化和再循环比表达hOXTR-376 R或hOXTR-376 C的细胞更快。此外，与表达标记有增强型绿色荧光蛋白（EGFP）的普通型hOXTR-376 R的细胞相比，在表达标记有增强型绿色荧光蛋白（EGFP）的hOXTR-376 G和hOXTR-376 C的细胞中，[Ca 2 +]i和IP 3形成的升高降低。这些结果表明，罕见的遗传变异rs35062132可能有助于ASD的发病机制，并可能提供一个个体差异的分子基础，在OXTR介导的社会行为的调节。
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. 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. 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>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>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’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’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. 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.
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影响因子：
4.9
作者：
Campbell, Daniel B.;Datta, Dibyadeep;Jones, Shaine T.;Lee, Evon Batey;Sutcliffe, James S.;Hammock, Elizabeth A. D.;Levitt, Pat
通讯作者：
Levitt, Pat
DOI：
10.1111/j.1749-6632.2009.04541.x
发表时间：
2009-01-01
期刊：
VALUES, EMPATHY, AND FAIRNESS ACROSS SOCIAL BARRIERS
影响因子：
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作者：
Ebstein, Richard P.;Israel, Salomon;Yirmiya, Nurit
通讯作者：
Yirmiya, Nurit
影响因子：
2.5
作者：
Jacob, Suma;Brune, Camille W.;Cook, Edwin H., Jr.
通讯作者：
Cook, Edwin H., Jr.
影响因子：
3.5
作者：
Liu, Xiaoxi;Kawamura, Yoshiya;Sasaki, Tsukasa
通讯作者：
Sasaki, Tsukasa
影响因子：
30.8
作者：
通讯作者：
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