Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter

Overview

Gitelman syndrome is a salt wasting tubulopathy caused by mutations in the SLC12A3 gene coding for the thiazide sensitive sodium chloride cotransporter. This disease mimics the chronic treatment with thiazide diuretics and is characterized by renal hypokalemia, low to normal blood pressure, hypocalciuria and hypomagnesemia. The purpose of this study is to determine whether the heterozygous carriers present the metabolic risks and/or the benefits of this disease.

Gitelman syndrome (GS), is an autosomal recessive salt wasting tubulopathy caused mainly by loss of function mutations in the SLC12A3 gene coding for the thiazide sensitive sodium-chloride cotransporter (NCC). Thus, GS mimics a chronic treatment with high doses of thiazide diuretics. NCC is expressed in the distal convoluted tubule, which is responsible for 7% of NaCl reabsorption. GS is the more frequent hereditary tubulopathie with estimated prevalence of 1/40000, which implicates that 1% of general population are heterozygous carriers (600 000 in France). Previous publications suggest that the apparently asymptomatic heterozygous carriers could present some clinical traits of GS or chronic thiazide treatment. These including: beneficial aspects (low blood pressure, low urinary calcium excretions) or metabolic risks (hypokalemia, insulin resistance). Nevertheless, these studies do not evaluate all the aspects and blood pressure was evaluated once in hospital setting. This study aims to compare home monitoring blood pressure; salt balance; potassium, glucose lipid and mineral metabolism and vascular function in 80 heterozygous carriers, 80 GS patients and 80 controls persons (without mutations in SLC12A3 gene).