Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies
Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies
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DOI：
10.1002/mgg3.24
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发表时间：
2013-11-01
影响因子：
2
通讯作者：
Cormand, Bru
中科院分区：
文献类型：
--
作者：
Carreno, Oriel;Corominas, Roser;Cormand, Bru
偏瘫性偏头痛（HM）是一种罕见的常染色体显性偏头痛的严重亚型，其特征是复杂的先兆，包括一定程度的运动无力。在家族性和散发性病例中检测到四个基因（CACNA 1A、ATP 1A 2、SCN 1A和PRRT 2）的突变。这种遗传和临床异质性疾病常伴有永久性共济失调、癫痫发作、精神发育迟滞和慢性进行性小脑萎缩。在这里，我们报告了突变筛查CACNA 1A和ATP 1A 2基因在18例HM患者。此外，使用定量方法在CACNA 1A中进行基因内拷贝数变异（CNV）分析。我们鉴定了四个先前描述的错义CACNA 1A突变（p.Ser218Leu、p.Thr501Met、p.Arg583Gln和p.Thr666Met）和ATP 1A 2基因中的两个错义变化，先前描述的p.Ala606Thr和新变体p.Glu825Lys。没有发现结构变异。这种遗传筛选允许鉴定超过30%的疾病等位基因，所有等位基因都以杂合状态存在。通过电生理学研究、细胞活力测定或Western印迹分析，研究了CACNA 1A-p. Thr 501 Met突变（先前仅描述与发作性共济失调相关）和ATP 1A 2-p. Glu 825 Lys的功能后果。我们的数据表明，这两种变异都是致病的。
Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.