Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation
Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation
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DOI：
10.1176/appi.ajp.163.9.1622
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发表时间：
2006-09-01
影响因子：
17.7
通讯作者：
Briault, Sylvain
中科院分区：
文献类型：
--
作者：
Laumonnier, Frederic;Roger, Sebastien;Briault, Sylvain
目的：自闭症是一种复杂的、很大程度上是遗传性精神疾病。在大多数情况下，自闭症的病因尚不清楚，但有强有力的证据表明遗传病因。为了识别候选基因，平衡染色体畸变的物理作图是一种强有力的策略，因为多种基因已在多种疾病中得到表征。在这项研究中，作者分析了自闭症和智力迟钝受试者中从头出现的平衡相互易位。方法：作者使用覆盖感兴趣区域的细菌人工染色体克隆，通过荧光原位杂交实验对平衡的 9q23/10q22 易位进行了物理绘图。结果：研究结果表明，KCNMA1 基因编码大电导 Ca2+ 激活的 K+ 的 α 亚基（ BKCa) 通道（神经元兴奋性的突触调节因子）受到物理破坏。进一步的分子和功能分析表明该基因的单倍体不足以及编码的 BKCa 通道的活性降低。通过添加 BKCa 通道开放剂 (BMS-204352) 可在体外增强此活性。对 116 名自闭症受试者的进一步突变分析发现，在比较受试者中未发现的蛋白质高度保守结构域中存在氨基酸取代。结论：这些结果表明 BKCa 通道的功能缺陷与自闭症障碍之间可能存在关联，并提出了突触传递缺陷可能导致自闭症和精神缺陷的病理生理学的假设。
Objective: Autism is a complex, largely genetic psychiatric disorder. In the majority of cases, the cause of autism is not known, but there is strong evidence for a genetic etiology. To identify candidate genes, the physical mapping of balanced chromosomal aberrations is a powerful strategy, since several genes have been characterized in numerous disorders. In this study, the authors analyzed a balanced reciprocal translocation arising de novo in a subject with autism and mental retardation.Method: The authors performed the physical mapping of the balanced 9q23/ 10q22 translocation by fluorescent in situ hybridization experiments using bacterial artificial chromosome clones covering the areas of interest.Results: Findings revealed that the KCNMA1 gene, which encodes the alpha- subunit of the large conductance Ca2+-activated K+ ( BKCa) channel, a synaptic regulator of neuronal excitability, is physically disrupted. Further molecular and functional analyses showed the haploinsufficiency of this gene as well as decreased activity of the coded BKCa channel. This activity can be enhanced in vitro by addition of a BKCa channel opener (BMS-204352). Further mutational analyses on 116 autistic subjects led to the identification of an amino acid substitution located in a highly conserved domain of the protein not found in comparison subjects.Conclusions: These results suggest a possible association between a functional defect of the BKCa channel and autistic disorder and raise the hypothesis that deficits in synaptic transmission may contribute to the physiopathology of autism and mental deficiency.