Schlingmann, Karl P. and Bandulik, Sascha and Mammen, Cherry and Tarailo-Graovac, Maja and Holm, Rikke and Baumann, Matthias and Koenig, Jens and Lee, Jessica J. Y. and Drogemoller, Britt and Imminger, Katrin and Beck, Bodo B. and Altmueller, Janine and Thiele, Holger and Waldegger, Siegfried and van't Hoff, William and Kleta, Robert and Warth, Richard and van Karnebeek, Clara D. M. and Vilsen, Bente and Bockenhauer, Detlef and Konrad, Martin (2018) Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability. AMERICAN JOURNAL OF HUMAN GENETICS, 103 (5). pp. 808-816. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)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 alpha 1 subunit (ATP1A1). Functional characterization of mutant Na+, K+-ATPase alpha 1 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 alpha 1 isoform of the Na+, K+-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SOMATIC MUTATIONS; ALPHA-SUBUNIT; ISOFORM; NA+,K+-ATPASE; NA,K-ATPASE; SODIUM; TRPM6; HYPEREXCITABILITY; INHIBITION; TRANSPORT; |
| Subjects: | 500 Science > 580 Botanical sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Pflanzenwissenschaften > Lehrstuhl für Zellbiologie und Pflanzenphysiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Oct 2019 09:42 |
| Last Modified: | 10 Oct 2019 09:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13631 |
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