Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients.
Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients.
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DOI：
10.1371/journal.pone.0056120
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hirose S
中科院分区：
文献类型：
--
作者：
Ishii A;Saito Y;Mitsui J;Ishiura H;Yoshimura J;Arai H;Yamashita S;Kimura S;Oguni H;Morishita S;Tsuji S;Sasaki M;Hirose S
儿童交替性偏瘫是一种罕见的疾病，其特征是短暂的轻瘫和认知功能障碍的反复发作。最近来自美国和欧洲的研究已经描述了AHC中的ATP 1A 3突变。然而，基因型-表型关系仍不清楚。本研究的目的是通过外显子组分析鉴定日本AHC队列中的遗传异常。8例散发性AHC患者共发现712 558个单核苷酸变异，经排除后，3个基因的突变被认为是AHC的候选病因。每例患者均携带ATP 1A 3的杂合错义突变，包括G755 C、E815 K、C927 Y和D801 N。所有突变均位于高度保守的氨基酸残基上，并推断影响相应ATP泵（ATP 1A 3的产物）的ATP酶活性。它们是新生突变，在96名健康志愿者中未发现。使用桑格测序，E815 K被发现在其他两个散发性AHC病例。在这项研究中，10名患者中有5名（50%）发现了E815 K，患病率高于最近两项研究报告的患病率[82名患者中有19名（23%），24名患者中有7名（29%）]。此外，受影响个体的临床数据表明，与其他ATP 1A 3突变相比，E815 K导致更高的表型。在本研究中检查的所有日本AHC患者中均发现了ATP 1A 3的杂合性新发突变，证实ATP 1A 3突变是AHC的病因。
Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC.
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影响因子：
30.8
作者：
De Fusco, M;Marconi, R;Casari, G
通讯作者：
Casari, G
影响因子：
5.3
作者：
MCGRAIL, KM;PHILLIPS, JM;SWEADNER, KJ
通讯作者：
SWEADNER, KJ
影响因子：
5.8
作者：
Saito, Taro L.;Yoshimura, Jun;Morishita, Shinichi
通讯作者：
Morishita, Shinichi
影响因子：
16.2
作者：
Aguiar, PD;Sweadner, KJ;Ozelius, LJ
通讯作者：
Ozelius, LJ
影响因子：
4
作者：
Bassi, MT;Bresolin, N;Casari, G
通讯作者：
Casari, G