Genetic and expression analyses reveal elevated expression of syntaxin 1A (STX1A) in high functioning autism
Genetic and expression analyses reveal elevated expression of syntaxin 1A (STX1A) in high functioning autism
复制标题
DOI：
10.1017/s1461145708009036
复制
发表时间：
2008-12-01
影响因子：
4.8
通讯作者：
Mori, Norio
中科院分区：
文献类型：
--
作者：
Nakamura, Kazuhiko;Anitha, Ayyappan;Mori, Norio
自闭症是一种在儿童早期诊断出的普遍性发育障碍。据报道，自闭症患者存在血清素能神经传递异常。血清素转运蛋白（5-HTT）调节血清素水平，是自闭症的主要治疗靶点。因此，调节 5-HTT 表达的因素可能与自闭症有关。一种候选 5-HTT 调节蛋白是突触前蛋白 Syntaxin 1A (STMA)。我们在一项三人关联研究中使用来自 249 名具有自闭症先证者的 AGRE 三人组的 DNA 样本检查了 STX1A 与自闭症的关联。由于自闭症在男性中更为普遍，因此只选择了男性先证者。 102名三人组的先证者智商>70，被认为是高功能自闭症（HFA）。在传递不平衡测试 (TDT) 分析中，rs2293485 (p = 0.034) 和 rs4717806 (p = 0.033) 显示与 HFA 名义相关；还观察到适度的单倍型关联。显示关联的 SNP 与早期发育异常 (ADI-R_D) 有关。我们进一步比较了未接受药物的 HFA 患者 (n = 12) 和年龄和性别匹配的对照 (n = 13) 淋巴细胞中的 STX1A mRNA 表达。 HFA 组中的 STX1A 表达显着高于对照组 (p = 0.001)。因此，我们提出 STX1A 在 HFA 发病机制中可能发挥的作用。在童年早期，有一段时期大脑血清素合成水平较高，但自闭症儿童的大脑血清素合成受到干扰。正如与 ADI-R_D 的关联所暗示的那样，STX1A 可能会影响神经发育这一阶段的血清素系统。
Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STMA). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p = 0.034) and rs4717806 (p = 0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n = 12) and age- and sex-matched controls (n = 13). STX1A expression in the HFA group was significantly higher (p = 0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neuro-development, as implied by the association with ADI-R_D.