Universität zu Köln

Schlingmann, Karl P., Bandulik, Sascha, Mammen, Cherry, Tarailo-Graovac, Maja ORCID: 0000-0002-4472-8584, Holm, Rikke, Baumann, Matthias, Koenig, Jens, Lee, Jessica J. Y., Drogemoller, Britt ORCID: 0000-0002-3348-5855, Imminger, Katrin, Beck, Bodo B., Altmueller, Janine, Thiele, Holger, Waldegger, Siegfried, van't Hoff, William, Kleta, Robert, Warth, Richard ORCID: 0000-0001-6084-0659, van Karnebeek, Clara D. M., Vilsen, Bente ORCID: 0000-0002-4727-9382, Bockenhauer, Detlef ORCID: 0000-0001-5878-941X and Konrad, Martin (2018). Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability. Am. J. Hum. Genet., 103 (5). S. 808 - 817. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schlingmann, Karl P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bandulik, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Mammen, Cherry UNSPECIFIED UNSPECIFIED UNSPECIFIED Tarailo-Graovac, Maja UNSPECIFIED orcid.org/0000-0002-4472-8584 UNSPECIFIED Holm, Rikke UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenig, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Jessica J. Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Drogemoller, Britt UNSPECIFIED orcid.org/0000-0002-3348-5855 UNSPECIFIED Imminger, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldegger, Siegfried UNSPECIFIED UNSPECIFIED UNSPECIFIED van't Hoff, William UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleta, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Warth, Richard UNSPECIFIED orcid.org/0000-0001-6084-0659 UNSPECIFIED van Karnebeek, Clara D. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vilsen, Bente UNSPECIFIED orcid.org/0000-0002-4727-9382 UNSPECIFIED Bockenhauer, Detlef UNSPECIFIED orcid.org/0000-0001-5878-941X UNSPECIFIED Konrad, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168001
DOI:	10.1016/j.ajhg.2018.10.004
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	103
Number:	5
Page Range:	S. 808 - 817
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SOMATIC MUTATIONS; ALPHA-SUBUNIT; ISOFORM; NA+,K+-ATPASE; NA,K-ATPASE; SODIUM; TRPM6; HYPEREXCITABILITY; INHIBITION; TRANSPORT Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16800