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Two mutations in the thiazide-sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report.

ABSTRACT: Background:Gitelman syndrome (GS) is considered as the most common renal tubular disorder, and we report the first Romanian patient with GS confirmed at molecular level and diagnosed according to genetic testing. Patient and methods:This paper describes the case of a 27-year-old woman admitted with severe hypokalemia, slight hypomagnesemia, hypocalcemia, hypocalciuria, metabolic alkalosis, hyperreninemia, low blood pressure, limb muscle weakness, marked fatigue and palpitations. Family history revealed a consanguineous family with autosomal-recessive transmission of GS with two cases over five generations. Results:Next-generation sequencing technology detected two different homozygous mutations c.1805_1806delAT and c.2660+1G>A in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl co-transporter, confirmed by the Sanger method. Conclusion:Clinicians should be aware of the existence of GS, manage the condition properly and consider the risk of disease recurrence to the next generations.

SUBMITTER: Gug C

PROVIDER: S-EPMC5784745 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Two mutations in the thiazide-sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report.

Gug Cristina C Mihaescu Adelina A Mozos Ioana I

Therapeutics and clinical risk management 20180122

<h4>Background</h4>Gitelman syndrome (GS) is considered as the most common renal tubular disorder, and we report the first Romanian patient with GS confirmed at molecular level and diagnosed according to genetic testing.<h4>Patient and methods</h4>This paper describes the case of a 27-year-old woman admitted with severe hypokalemia, slight hypomagnesemia, hypocalcemia, hypocalciuria, metabolic alkalosis, hyperreninemia, low blood pressure, limb muscle weakness, marked fatigue and palpitations. F ...[more]

PMID: 29403282

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Project description:BackgroundThe potassium channel Kir4.1 forms the Kir4.1/Kir5.1 heterotetramer in the basolateral membrane of the distal convoluted tubule (DCT) and plays an important role in the regulation of the thiazide-sensitive NaCl cotransporter (NCC). Kidney-specific deletion of the ubiquitin ligase Nedd4-2 increases expression of NCC, and coexpression of Nedd4-2 inhibits Kir4.1/Kir5.1 in vitro. Whether Nedd4-2 regulates NCC expression in part by regulating Kir4.1/Kir5.1 channel activity in the DCT is unknown.MethodsWe used electrophysiology studies, immunoblotting, immunostaining, and renal clearance to examine Kir4.1/Kir5.1 activity in the DCT and NCC expression/activity in wild-type mice and mice with kidney-specific knockout of Nedd4-2, Kir4.1, or both.ResultsDeletion of Nedd4-2 increased the activity/expression of Kir4.1 in the DCT and also, hyperpolarized the DCT membrane. Expression of phosphorylated NCC/total NCC and thiazide-induced natriuresis were significantly increased in the Nedd4-2 knockout mice, but these mice were normokalemic. Double-knockout mice lacking both Kir4.1/Kir5.1 and Nedd4-2 in the kidney exhibited increased expression of the epithelial sodium channel α-subunit, largely abolished basolateral potassium ion conductance (to a degree similar to that of kidney-specific Kir4.1 knockout mice), and depolarization of the DCT membrane. Compared with wild-type mice, the double-knockout mice displayed inhibited expression of phosphorylated NCC and total NCC and had significantly blunted thiazide-induced natriuresis as well as renal potassium wasting and hypokalemia. However, NCC expression/activity was higher in the double-knockout mice than in Kir4.1 knockout mice.ConclusionsNedd4-2 regulates Kir4.1/Kir5.1 expression/activity in the DCT and modulates NCC expression by Kir4.1-dependent and Kir4.1-independent mechanisms. Basolateral Kir4.1/Kir5.1 activity in the DCT partially accounts for the stimulation of NCC activity/expression induced by deletion of Nedd4-2.

Dataset Information

Two mutations in the thiazide-sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report.

Publications

Two mutations in the thiazide-sensitive NaCl co-transporter gene in a Romanian Gitelman syndrome patient: case report.

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