Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Am J Hum Genet. 2018 Nov 1;103(5):808-816. doi: 10.1016/j.ajhg.2018.10.004.

Karl P Schlingmann ¹, Sascha Bandulik ², Cherry Mammen ³, Maja Tarailo-Graovac ⁴, Rikke Holm ⁵, Matthias Baumann ⁶, Jens König ⁷, Jessica J Y Lee ⁸, Britt Drögemöller ⁸, Katrin Imminger ², Bodo B Beck ⁹, Janine Altmüller ¹⁰, Holger Thiele ¹⁰, Siegfried Waldegger ⁶, William Van't Hoff ¹¹, Robert Kleta ¹², Richard Warth ², Clara D M van Karnebeek ¹³, Bente Vilsen ⁵, Detlef Bockenhauer ¹², Martin Konrad ⁷

Affiliations

1 Department of General Pediatrics, University Children's Hospital, Münster 48149, Germany. Electronic address: [email protected].
2 Medical Cell Biology, University of Regensburg, Regensburg 93053, Germany.
3 Division of Nephrology, Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada.
4 Departments of Biochemistry, Molecular Biology, and Medical Genetics, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
5 Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark.
6 Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
7 Department of General Pediatrics, University Children's Hospital, Münster 48149, Germany.
8 Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
9 Institute of Human Genetics, University of Cologne, Cologne 50931, Germany; Center for Molecular Medicine Cologne, Cologne 50931, Germany; Center for Rare and hereditary Kidney Disease, Cologne 50931, Germany.
10 Cologne Center for Genomics, University of Cologne, Cologne 50931, Germany.
11 Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
12 Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK; UCL Centre for Nephrology, London NW3 2PF, UK.
13 Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Departments of Pediatrics and Clinical Genetics, Amsterdam University Medical Center, Amsterdam, 1007, the Netherlands.

PMID: 30388404 DOI: 10.1016/j.ajhg.2018.10.004

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; hypomagnesemia; intellectual disability; seizures; α1 subunit.

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