Nat Gene：ATP1A3基因突变引发儿童交替性偏瘫

儿童交替性偏瘫（AHC）是一种非常罕见的瘫痪疾病，常常引发机体一侧冻结，近日，来自杜克大学的研究者发现了一种基因的突变在大多数被诊断患有AHC疾病的患者中可以引发相应的病症。由于研究者发现了导致该疾病的根源问题，因此开发可行性的治疗方法变得很有希望，相关研究成果刊登在了7月29日的国际杂志Nature Genetics上。

AHC是一种散发性的疾病，研究者比对了7个AHC病人的基因组以及其正常父母的基因组，当研究者在所有患病者机体中发现了相同的突变的时候，研究者表示他们找到了疾病的发病根源。发生突变的基因编码ATP1A3，ATP1A3是一个关键的转移分子，通过跨越神经元之间的通道来转移钠离子和钾离子，最终调节大脑活力。

研究者Arn van表示，这项研究是一个优秀的例子，揭示了遗传研究如何指导世界标尺来在如此罕见的疾病中指出差异所在。许多年之间，研究者的研究证明了AHC是由遗传因子引发的，但是直到现在，研究者仍然不清楚潜在基因的异常所在。

ATP1A3的突变促发AHC将会增加研究者对疾病的认识，使得医生们更加正确地诊断该疾病。研究者Mikati表示，未来我们将开发新的药物来治疗此疾病，我们将看到通过特殊的突变检测方法所带来的检测快速效应，直接检测方法将避免误诊以及患者的不正当用药。

编译自：Gene Discovery Set to Help With Mysterious Paralysis of Childhood

doi:10.1038/ng.2358
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De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Erin L Heinzen,1, 2, 35 Kathryn J Swoboda,3, 4, 35 Yuki Hitomi,1, 35 Fiorella Gurrieri,5 Sophie Nicole,6, 7, 8 Boukje de Vries,9 F Danilo Tiziano,5 Bertrand Fontaine,6, 7, 8, 10 Nicole M Walley,1 Sinéad Heavin,11 Eleni Panagiotakaki,12 European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium,13 Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium,13 European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium,13 Stefania Fiori,5 Emanuela Abiusi,5 Lorena Di Pietro,5 Matthew T Sweney,3 Tara M Newcomb,3 Louis Viollet,4 Chad Huff,14 Lynn B Jorde,14 Sandra P Reyna,4 Kelley J Murphy,4 Kevin V Shianna,1, 2 Curtis E Gumbs,1 Latasha Little,1 Kenneth Silver,15, 16 Louis J Ptáček,17, 18 Joost Haan,19, 20 Michel D Ferrari,20 Ann M Bye,21 Geoffrey K Herkes,22 Charlotte M Whitelaw,23 David Webb,24 Bryan J Lynch,25 Peter Uldall,26 Mary D King,25 Ingrid E Scheffer,11, 27, 28 Giovanni Neri,5 Alexis Arzimanoglou,12, 29, 30 Arn M J M van den Maagdenberg,9, 20 Sanjay M Sisodiya,31, 36 Mohamad A Mikati32, 33, 36 & David B Goldstein1, 34, 36 et al.

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.