A Novel Homozygous KLHL3 Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life.

Autor:	Etges A; Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Hellmig N; Department of Nephrology and Medical Intensive Care, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Center of Functional Genomics, Berlin, Germany., Walenda G; Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Haddad BG; Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany., Machtens JP; Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany.; Institute of Clinical Pharmacology, RWTH Aachen University, Aachen, Germany., Morosan T; DaVita Dialysezentrum Dormagen, Dormagen, Germany., Rump LC; Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Scholl UI; Department of Nephrology, School of Medicine, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.; Department of Nephrology and Medical Intensive Care, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Center of Functional Genomics, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Nephron [Nephron] 2022; Vol. 146 (4), pp. 418-428. Date of Electronic Publication: 2022 Jan 28.
DOI:	10.1159/000521626
Abstrakt:	Introduction: Pseudohypoaldosteronism type II (PHA II) is a Mendelian disorder, featuring hyperkalemic acidosis and low plasma renin levels, typically associated with hypertension. Mutations in WNK1, WNK4, CUL3, and KLHL3 cause PHA II, with dominant mutations in WNK1, WNK4, and CUL3 and either dominant or recessive mutations in KLHL3. Fourteen families with recessive KLHL3 mutations have been reported, with diagnosis at the age of 3 months to 56 years, typically in individuals with normal kidney function. Methods: We performed clinical and genetic investigations in a patient with hyperkalemic hypertension and used molecular dynamics simulations, heterologous expression in COS7 cells, and Western blotting to investigate the effect of a KLHL3 candidate disease mutation on WNK4 protein expression. Results: The patient, a 58-year-old woman from a consanguineous family, showed hypertension, persistent hyperkalemic acidosis associated with severe muscle pain, nephrolithiasis, chronic kidney disease (CKD), and coronary heart disease. Therapy with hydrochlorothiazide corrected hyperkalemia, hypertension, and muscle pain. Genetic analysis revealed a homozygous p.Arg431Trp mutation at a highly conserved KLHL3 position. Simulations suggested reduced stability of the mutant protein, which was confirmed by Western blot. Compared with wild-type KLHL3, cotransfection of p.Arg431Trp KLHL3 led to increased WNK4 protein levels, inferred to cause increased NaCl reabsorption via the thiazide-sensitive carrier and PHA II. Conclusions: Even in patients presenting late in life and in the presence of CKD, PHA II should be suspected if renin levels are low and hyperkalemic acidosis and hypertension are inadequate for CKD stage, particularly in the presence of a suspicious family history. (© 2022 The Author(s) Published by S. Karger AG, Basel.)
Databáze:	MEDLINE
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