Department of General Pediatrics, University Children's Hospital, Münster 48149, Germany.
Medical Cell Biology, University of Regensburg, Regensburg 93053, Germany.
Am J Hum Genet. 2018 Nov 1;103(5):808-816. doi: 10.1016/j.ajhg.2018.10.004.
Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na, K-ATPase α1 subunit (ATP1A1). Functional characterization of mutant Na, K-ATPase α1 subunits in heterologous expression systems revealed not only a loss of Na, K-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the α1 isoform of the Na, K-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.
在过去的几十年中，越来越多的人类镁稳态单基因疾病在临床上得到了表征，对受影响个体的遗传研究确定了细胞和上皮镁转运的重要分子成分。在这里，我们描述了三个来自非近亲家庭的婴儿，他们表现出一种疾病表型，包括婴儿期全身性癫痫发作、严重低镁血症和肾脏镁丢失。尽管补充了镁，但癫痫仍持续存在，并伴有明显的智力残疾。全外显子组测序和常规 Sanger 测序发现催化 Na+、K+-ATPase α1 亚基（ATP1A1）的杂合新生突变。在异源表达系统中对突变 Na+、K+-ATPase α1 亚基的功能特征分析不仅揭示了 Na+、K+-ATPase 功能的丧失，还揭示了异常的阳离子通透性，导致膜去极化，可能加重了生理泵活性丧失的影响。这些发现强调了 Na+、K+-ATPase 的 α1 同工型对肾脏管状镁处理和细胞离子稳态以及维持生理神经元活动的不可或缺的作用。
