Germline de novo mutations in ATP1A1 cause renal hypomagnesemia, refractory seizures, and intellectual disability

Item Type:	Article
Title:	Germline de novo mutations in ATP1A1 cause renal hypomagnesemia, refractory seizures, and intellectual disability
Creators Name:	Schlingmann, K.P. and Bandulik, S. and Mammen, C. and Tarailo-Graovac, M. and Holm, R. and Baumann, M. and König, J. and Lee, J.J.Y. and Drögemöller, B. and Imminger, K. and Beck, B.B. and Altmüller, J. and Thiele, H. and Waldegger, S. and Van't Hoff, W. and Kleta, R. and Warth, R. and van Karnebeek, C.D.M. and Vilsen, B. and Bockenhauer, D. and Konrad, M.
Abstract:	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.
Keywords:	ATP1A1, Na-K ATPase, α1 Subunit, Hypomagnesemia, Seizures, Intellectual Disability
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	103
Number:	5
Page Range:	808-816
Date:	1 November 2018
Official Publication:	https://doi.org/10.1016/j.ajhg.2018.10.004
PubMed:	View item in PubMed

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