Sweadner Kathleen J, Arystarkhova Elena, Penniston John T, Swoboda Kathryn J, Brashear Allison, Ozelius Laurie J
Department of Neurosurgery (K.J. Sweadner, E.A., J.T.P.), Center for Human Genetics Research (K.J. Swoboda), and Department of Neurology, (K.J. Swoboda, L.J.O.) Massachusetts General Hospital, Boston; and the Department of Neurology (A.B.), Wake Forest School of Medicine, Winston-Salem, NC.
Neurol Genet. 2019 Feb 4;5(1):e303. doi: 10.1212/NXG.0000000000000303. eCollection 2019 Feb.
We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases , , and .
Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology.
Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in were absent from patient data. The known variants in fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites.
Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in that correlates with neurologic outcomes. The absence of "severe" pathogenic variants in patients predicts that they will manifest either in a different tissue or by death in utero and that new variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.
我们通过分析一个对神经系统有高度影响且序列同一性高的基因家族（Na,K - ATP酶α1、α2和α3）中的200多个致病变异，来检验密切相关的基因应具有相似致病变异的假设。
比较疾病相关变异的数据集。利用它们在蛋白质晶体结构中的等效位置来深入了解致病性，并与表型和同源性保守性相关联。
相对较少的突变影响了两个基因中的相应氨基酸。在α1（主要在神经元中表达）的膜结构域中，产生较轻神经表型的变异与产生严重表型的变异具有不同的结构位置。在α2（主要在星形胶质细胞中表达）中，患者数据中不存在α1中严重表型所特有的膜结构域变异。α3中的已知变异分为两个不同的组。序列保守性是一个不完美的指标：它在不同的结构域中有所不同，一些已证明具有致病性的变异位于保守性较低的位点。
尽管序列同一性高，但基因之间的致病变异各不相同，并且在Na,K - ATP酶α1中存在与神经学结果相关的基因型 - 结构 - 表型关系。α2患者中不存在“严重”致病变异预示着它们将在不同组织中表现出来或在子宫内死亡，并且新的α2变异将产生其他表型。重要的是，一些位于保守性较差的氨基酸中的变异仍然具有致病性，可能会被错误地预测为良性。
