Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2)
Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2)
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DOI：
10.1002/ajmg.b.30168
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发表时间：
2005-05-05
影响因子：
2.8
通讯作者：
McMahon, W
中科院分区：
文献类型：
--
作者：
Coon, H;Dunn, D;McMahon, W
我们报告了样本中的自闭症与最近描述的大脑表达的色氨酸羟化酶基因（TPH2）之间可能存在的关联。血清素神经递质系统在自闭症中的广泛复制激发了人们对血清素途径中许多基因的兴趣，这些基因可能是导致自闭症易感性的突变的候选者。血清素合成由限速酶色氨酸羟化酶控制。对原始色氨酸羟化酶基因 (TPH1) 和新异构体 (TPH2) 的小鼠研究表明，TPH1 主要在外周表达，而 TPH2 仅在脑组织中表达。我们搜索了覆盖TPH2所有11个外显子的6,467个核苷酸的人类序列变异，以及起始密码子上游的248个核苷酸和终止密码子下游的935个核苷酸。在我们两个中心研究的 88 名自闭症受试者和 95 名不相关的对照受试者中，描述了 18 种变异。使用无模型关联方法和经验 P 值估计，两种变异显示自闭症和对照受试者之间的频率差异（内含子 1 中的 T-G 变异 P=0.01，内含子 4 中的 A-T 变异 P=0.02）。包含这些变体的单倍型显示显着性略有增加（P=0.005）。对临床表型的进一步研究表明，这两个 SNP 变异的存在与描述重复和刻板行为的自闭症诊断访谈 (ADI) 领域的较高分数之间可能存在关联 (P=0.007)。我们得出的结论是，TPH2 可能在自闭症易感性中发挥一定作用，可能与重复行为特别相关，有待该结果的重复。 (c) 2005 年 Wiley-Liss, Inc.
We report a possible association between autism in our sample and a recently described brain-expressed tryptophan hydroxylase gene (TPH2). The well-replicated involvement of the serotonin neurotransmitter system in autism has stimulated interest in many genes in the serotonin pathway as possible candidates for mutations leading to autism susceptibility. Serotonin synthesis is controlled by the rate-limiting enzyme tryptophan hydroxylase. A mouse study of the original tryptophan hydroxylase gene (TPH1) and the new isoform (TPH2) showed that while TPH1 is primarily expressed peripherally, TPH2 is found exclusively in brain tissue. We searched for human sequence variants in 6,467 nucleotides covering all 11 exons of TPH2, and also 248 nucleotides upstream of the start codon, and 935 nucleotides downstream of the stop codon. Eighteen variants were characterized in 88 subjects with autism studied at our two centers, and 95 unrelated control subjects. Using a model-free association method and empirical P value estimation, two variants showed frequency differences between autism and control subjects (P=0.01 for a T-G variant in intron 1, and P=0.02 for a A-T variant in intron 4). A haplotype including these variants showed slightly increased significance (P=0.005). Further investigation of clinical phenotypes showed a possible association between presence of the variants at these two SNPs and higher scores on the Autism Diagnostic Interview (ADI) domain describing repetitive and stereotyped behaviors (P=0.007). We conclude that TPH2 may play a modest role in autism susceptibility, perhaps relating specifically to repetitive behaviors, pending replication of this result. (c) 2005 Wiley-Liss, Inc.