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首页> 外文期刊>BMC Medical Genomics >Mutation screening of melatonin-related genes in patients with autism spectrum disorders
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Mutation screening of melatonin-related genes in patients with autism spectrum disorders

机译：自闭症谱系障碍患者褪黑激素相关基因的突变筛选

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Background One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene. Methods In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample. Results Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A , and MTNR1B . Conclusions Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.
机译：背景自闭症谱系障碍（ASD）的一项一致发现是松果体激素褪黑激素水平下降，最近已证明，这种下降很大程度上是由于乙酰5-羟色胺O-甲基转移酶（ASMT）的活性低所致。褪黑激素合成途径中的最后一种酶。而且，已经鉴定出ASMT基因中的突变，包括剪接位点突变，其与低ASMT活性和褪黑激素分泌有关，这表明自闭症中观察到的低ASMT活性至少部分是由于ASMT基因内的变异所致。 。方法在本研究中，我们通过突变筛选AA-NAT（芳基烷基胺N-乙酰基转移酶），ASMT，MTNR1A，MTNR1B（褪黑激素受体1A和1B）和GPR50（G蛋白偶联）来研究褪黑激素途径中的所有基因。 109例患有自闭症谱系障碍（ASD）的患者，同时编码合成酶和褪黑激素的三个主要受体。将来自普通人群的188名受试者作为比较组，并对患者样品中鉴定出的变异进行基因分型。结果在ASD患者中发现了几种罕见的变异，包括先前报道的ASMT剪接位点突变（IVS5 + 2T> C）。在影响蛋白质序列的变体中，在我们的比较组中只有MTNR1B基因中的V124I不存在。但是，在研究的三个基因ASMT，MTNR1A和MTNR1B的上游调控区中发现了突变。结论我们关于另一位在ASMT中带有剪接位点突变IVS5 + 2T> C的ASD患者的报告进一步支持了该基因参与自闭症。此外，我们的结果还表明，其他与褪黑激素相关的基因可能是寻找与自闭症谱系障碍和相关神经行为表型有关的基因的进一步研究的有趣候选对象。但是，有必要对本研究中发现的新变异进行进一步研究，以阐明它们在这些疾病的病理生理中的潜在作用。

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