ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features.
ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features.
复制标题
DOI：
10.3389/fped.2021.657256
复制
发表时间：
2021
影响因子：
2.6
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Lin Z;Li J;Ji T;Wu Y;Gao K;Jiang Y
背景：ATP 1A 1编码Na+/K+-ATP酶的α1亚型，在肾脏和中枢神经系统大量表达。ATP 1A 1变异体可能导致Na+/K+-ATP酶功能丧失，并导致广泛的表型。本研究旨在总结ATP 1A 1从头突变相关疾病的临床和遗传特征，并探讨表型和基因型之间的潜在相关性。方法：我们分析了两个新的案件窝藏新的从头ATP 1A 1变异，并审查了所有报告的情况。结果：两例先证者均表现为发育迟缓，1例伴睡眠障碍、易激惹，2例伴难治性癫痫发作。它们各自具有新的从头杂合错义变体，分别为c.2797G>A[p.Asp933Asn]（NM_000701）和c.2590G>A[p.Gly864Arg]（NM_000701）。在之前的两篇论文中报告了4例新发ATP 1A 1变异患者。其中3例为难治性癫痫发作，1例为复杂性遗传性痉挛性截瘫（HSP）。因此，所有6名患者都有发育迟缓，其中4名患有癫痫。所有变异体均位于ATP 1A 1蛋白的跨膜区M3、M4、M7和M8。M3和M7突变的4例患者具有更严重的表型，包括发育迟缓和癫痫性脑病，其中3例具有低镁血症，而M4和M8突变的2例患者具有较轻的表型，仅具有轻度发育迟缓，没有癫痫发作或低镁血症。纠正低镁血症并没有控制这些癫痫发作。结论：两个新的从头ATP 1A 1变异体在两名患者中发现，丰富了ATP 1A 1突变相关疾病的基因型和表型谱。我们的研究结果表明，低镁血症在这种疾病可能与更严重的表型，并表明更严重的Na+/K+-ATP酶功能障碍。M3和M7跨膜区的变异与更严重的表型相关，提示M3和M7的变异可能导致更严重的ATP 1A 1功能缺陷。
Background: ATP1A1 encodes an α1 isoform of Na+/K+-ATPase, which is expressed abundantly in kidneys and central nervous system. ATP1A1 variants may cause Na+/K+-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of ATP1A1 de novo mutation-related disorders and explore the potential correlations between phenotypes and genotypes. Methods: We analyzed two new cases harboring novel de novo ATP1A1 variants and reviewed all reported cases. Results: Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability, and patient 2 with refractory seizures. They each had a novel de novo heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with de novo ATP1A1 variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP). Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures. Conclusions: Two novel de novo ATP1A1 variants identified in two patients here enriched the genotypic and phenotypic spectrum of ATP1A1 mutation-related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na+/K+-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe ATP1A1 functional defect.
登录
查看更多内容
影响因子：
30.8
作者：
Azizan, Elena A. B.;Poulsen, Hanne;Brown, Morris J.
通讯作者：
Brown, Morris J.
影响因子：
4.4
作者：
YANG-FENG T L;SCHNEIDER J W;FRANCKE U
通讯作者：
FRANCKE U
影响因子：
4
作者：
Holm TH;Lykke-Hartmann K
通讯作者：
Lykke-Hartmann K
影响因子：
8.3
作者：
Williams, Tracy Ann;Monticone, Silvia;Mulatero, Paolo
通讯作者：
Mulatero, Paolo
影响因子：
3.5
作者：
Stregapede, Fabrizia;Travaglini, Lorena;Nicita, Francesco
通讯作者：
Nicita, Francesco