Sodium channels SCN1A, SCN2A and SCN3A in familial autism
Sodium channels SCN1A, SCN2A and SCN3A in familial autism
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DOI：
10.1038/sj.mp.4001241
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发表时间：
2003-01-01
影响因子：
11
通讯作者：
Meisler, MH
中科院分区：
文献类型：
--
作者：
Weiss, LA;Escayg, A;Meisler, MH
自闭症是一种精神疾病，估计遗传率为90%。三分之一的自闭症患者经历过癫痫发作。在2号染色体上的一组电压门控钠通道基因附近发现了一个自闭症易感位点。其中两个基因SCN1A和SCN2A的突变会导致癫痫发作障碍GEFS +。为了评估这些钠通道基因作为自闭症易感位点的候选基因，我们在117个多重自闭症家庭中筛选了编码外显子和剪接位点的变异。共筛选出27 kb的编码序列和3 kb的内含子序列。只有6个家族携带对钠通道功能有潜在影响的变异。在单个家族中分别观察到5个编码变异体和1个分枝点突变，但在对照组中不存在。SCN2A的变体R1902C位于钙调蛋白结合位点，并被发现降低钙结合钙调蛋白的结合亲和力。在一个自闭症家庭中观察到SCN1A中的R542Q，并且先前在一名青少年肌阵挛性癫痫患者中被发现。在培养的淋巴细胞中检测了支点突变的影响。需要进一步的种群研究和功能测试来评估编码位点变异和幼虫位点变异的致病性。筛选的基因组序列SNP密度为1/kb。我们报告了38个钠通道snp，这些snp将在未来的关联和连锁研究中有用。
Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS +. To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.