Mutation screening of melatonin-related genes in patients with autism spectrum disorders.
Mutation screening of melatonin-related genes in patients with autism spectrum disorders.
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自闭症谱系障碍患者中褪黑激素相关基因的突变筛查。
DOI：
10.1186/1755-8794-3-10
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发表时间：
2010-04-08
影响因子：
2.7
通讯作者：
Melke J
中科院分区：
文献类型：
--
作者：
Jonsson L;Ljunggren E;Bremer A;Pedersen C;Landén M;Thuresson K;Giacobini M;Melke J
在自闭症谱系障碍(ASD)中，一个一致的发现是松果体激素褪黑激素水平下降，最近的研究表明，这种下降在很大程度上是由于褪黑激素合成途径中的最后一种酶--乙酰5-羟色胺O-甲基转移酶(ASMT)活性低所致。此外，已发现ASMT基因的突变，包括与ASMT活性低和褪黑激素分泌有关的剪接点突变，这表明自闭症患者ASMT活性低至少部分是由于ASMT基因内的变异。在本研究中，我们通过对109例自闭症谱系障碍(ASD)患者的AA-NAT(芳基烷胺N-乙酰基转移酶)、ASMT、MTNR1A、MTNR1B(褪黑素受体1A和1B)和GPR50(G蛋白偶联受体50)的突变筛选，研究了与褪黑激素途径有关的所有基因。来自普通人群的188名受试者被用作对照组，并对患者样本中确定的变异进行了基因分型。在ASD患者中发现了几个罕见的变异，包括先前报道的ASMT(IVS5+2T>；C)剪接位点突变。在影响蛋白质序列的变异中，只有MTNR1B基因的V124I在我们的对照组中缺失。然而，在所研究的三个基因ASMT、MTNR1A和MTNR1B的上游调控区发现了突变。我们报告的另一名ASD患者在ASMT中携带剪接点突变IVS5+2T>；C，进一步支持该基因与自闭症的关系。此外，我们的结果还表明，其他褪黑素相关基因可能是进一步研究与自闭症谱系障碍和相关神经行为表型相关的基因的有趣候选基因。然而，有必要对这项研究中确定的新变种进行进一步研究，以阐明它们在这些疾病的病理生理学中的潜在作用。
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. 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. 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. 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.
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影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
1.9
作者：
Garstang, J.;Wallis, M.
通讯作者：
Wallis, M.
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M
影响因子：
6.9
作者：
Fombonne, E
通讯作者：
Fombonne, E
影响因子：
34.7
作者：
Cirelli, Chiara
通讯作者：
Cirelli, Chiara