Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability #MMPMID30388404
Schlingmann KP; Bandulik S; Mammen C; Tarailo-Graovac M; Holm R; Baumann M; Konig J; Lee JJY; Drogemoller B; Imminger K; Beck BB; Altmuller J; Thiele H; Waldegger S; Van't Hoff W; Kleta R; Warth R; van Karnebeek CDM; Vilsen B; Bockenhauer D; Konrad M
Am J Hum Genet 2018[Nov]; 103 (5): 808-816 PMID30388404show ga
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 alpha1 subunit (ATP1A1). Functional characterization of mutant Na(+), K(+)-ATPase alpha1 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 alpha1 isoform of the Na(+), K(+)-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.
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Am+J+Hum+Genet 2018 ; 103 (5): 808-816
