Diseases caused by mutations in the Na⁺/K⁺ pump α1 gene ATP1A1

Abstract

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.

The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot–Marie–Tooth disease

“…6 ATP1A1 protein and respective locations of the pathogenic variants reported up to date. Variants written in black represent CMT related variants identified in other studies, red represents the ATP1A1 variant identified in this study, blue represent hypomagnesaemia and intellectual disability or spastic paraplegia, green represent developmental delay, orange represent complex neurodevelopmental syndrome diseases associated with Na + /K + ATPase mutations [34]. Mitochondria are essential for buffering intracellular Ca 2+ .…”

The role of Na+‐K+‐ATPasein the epileptic brain

“…In addition, homozygous truncating variants of ATP1A2 would cause a novel lethal recognizable polymicrogyria syndrome. Polymicrogyria is responsible for a wide range of neurological symptoms, including epilepsy 36–38 . The mechanism under epileptogenicity of polymicrogyria remains unknown.…”

“…Polymicrogyria is responsible for a wide range of neurological symptoms, including epilepsy. 36 , 37 , 38 The mechanism under epileptogenicity of polymicrogyria remains unknown. However, unilateral multilobar polymicrogyria is often relevant to an age‐related syndrome of epilepsy.…”

ATP1A1-linked diseases require a malfunctioning protein product from one allele

“…Heterozygous loss-of-function, with a missense variant that partially reduces Na + /K +transport by the gene product of one allele, has been proposed to cause some ATP1A1 disease phenotypes. Electrophysiological studies in Xenopus oocytes and adrenal NCI-H295R cells expressing disease-related NKA α1 variants reported depolarizing inward currents through most (but not all) variants linked to hyperaldosteronism (2,8,10,11) or hypomagnesemia with refractory seizures (7,12), providing a plausible gain-of-function mechanism for these diseaseassociated variants. However, variants causing neuropathies seem to lack such inward "leak" currents (4)(5)(6)(7)(9)(10)(11).…”