A novel sodium channel mutation in a family with hypokalemic periodic paralysis
A novel sodium channel mutation in a family with hypokalemic periodic paralysis
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DOI：
10.1212/wnl.53.9.1932
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发表时间：
1999-12-10
期刊：
影响因子：
9.9
通讯作者：
Ebers, GC
中科院分区：
文献类型：
--
作者：
Bulman, DE;Scoggan, KA;Ebers, GC
目的：探讨S病不是由二氢吡啶敏感受体α(1)亚单位基因突变引起的低血钾性周期性麻痹的病因。背景：低血钾性周期性麻痹主要由CACNA1S基因突变引起。HOKPP的遗传异质性已有报道，但尚未发现其他基因座。方法：采用单链构象多态(SSCP)分析和聚合酶链式反应(PCR)直接测序的方法，对该家系中骨骼肌α(1)-钠通道基因(SCN4A)进行突变筛查。结果：SSCP分析显示在第12外显子有一个异常迁移的构象，直接测序显示该构象在cDNA2006位发生了鸟嘌呤到腺嘌呤的转变，这导致了669位氨基酸从高度保守的精氨酸(Arg)变成了组氨酸(His)。这种序列改变只与受影响的家族成员分离，在来自健康对照组的100个DNA样本中没有发现。氨基酸的取代改变了跨膜片段DII/S4中最外层的正电荷，参与了电压敏感。结论：骨骼肌钠通道中DiI/S4和DIV/S4中的第一精氨酸和L钙通道基因CACNA1S似乎对正常功能起关键作用。在所有四种情况下，Arg到His的突变都会导致疾病表型。鉴定骨骼肌钠通道内的突变导致低血钾周期性麻痹是一项新的发现。
Objective: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease s not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha(1)-subunit gene (CACNA1S). Background: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. Methods: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha(1)-sodium channel gene (SCN4A) for a mutation in our family. Results: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. Conclusions: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel gene CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.