Human cell survival requires function of the Na⁺/K⁺ pump; the heteromeric protein that hydrolyzes ATP to extrude Na⁺ and import K⁺ across the plasmalemma, thereby building and maintaining their electrochemical gradients. Numerous dominant diseases caused by mutations in genes encoding for Na⁺/K⁺ pump catalytic (α) subunit isoforms highlight the importance of this protein. Here, we review literature describing disorders caused by missense mutations in ATP1A1, the gene encoding the ubiquitously expressed α1 isoform of the Na⁺/K⁺ pump. These various maladies include primary aldosteronism with secondary hypertension, an endocrine syndrome, Charcot-Marie-Tooth disease, a peripheral neuropathy, complex spastic paraplegia, another neuromuscular disorder, as well as hypomagnesemia accompanied by seizures and cognitive delay, a condition affecting the renal and central nervous systems. This article focuses on observed commonalities among these mutations' functional effects, as well as on the special characteristics that enable each particular mutation to exclusively affect a certain system, without affecting others. In this respect, it is clear how somatic mutations localized to adrenal adenomas increase aldosterone production without compromising other systems. However, it remains largely unknown how and why some but not other de novo germline or familial mutations (where the mutant must be expressed in numerous tissues) produce a specific disease and not the others. We propose hypotheses to explain this observation and the approaches that we think will drive future research on these debilitating disorders to develop novel patient-specific treatments by combining the use of heterologous protein-expression systems, patient-derived pluripotent cells, and gene-edited cell and mouse models.

中文翻译：

---

Na+/K+泵α1基因ATP1A1突变引起的疾病

人体细胞存活需要Na ⁺ /K ⁺泵的功能；^{水解 ATP 以挤出 Na +}并通过质膜导入 K ⁺的异聚蛋白，从而建立和维持它们的电化学梯度。^{由编码 Na +} /K ⁺泵催化 (α) 亚基同种型的基因突变引起的许多显性疾病突出了这种蛋白质的重要​​性。在这里，我们回顾了描述由 ATP1A1 错义突变引起的疾病的文献，ATP1A1 是编码广泛表达的 Na ⁺ /K ^{+ α1 同种型的基因}泵。这些不同的疾病包括原发性醛固酮增多症伴继发性高血压、内分泌综合征、Charcot-Marie-Tooth 病、周围神经病变、复杂的痉挛性截瘫、另一种神经肌肉疾病，以及伴有癫痫发作和认知迟缓的低镁血症，这是一种影响肾脏和中枢神经系统。本文着重于观察到这些突变的功能影响之间的共性，以及使每个特定突变能够专门影响某个系统而不影响其他系统的特殊特征。在这方面，很清楚定位于肾上腺腺瘤的体细胞突变如何在不损害其他系统的情况下增加醛固酮的产生。然而，在很大程度上仍不清楚某些而非其他从头生殖系或家族突变（其中突变体必须在许多组织中表达）如何以及为什么会产生特定疾病而不是其他疾病。我们提出假设来解释这一观察结果以及我们认为将推动对这些衰弱性疾病的未来研究的方法，通过结合使用异源蛋白质表达系统、患者衍生的多能细胞和基因编辑细胞来开发新的患者特异性治疗方法和鼠标模型。