Identification of novel compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman's syndrome exhibiting Bartter's syndrome-liked phenotypes

Abstract Background Gitelman's syndrome (GS) is a rare salt-losing renal tubular disorder associated with SLC12A3 gene mutations, which encodes the Na-Cl co-transporter (NCCT). GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia, hypocalciuria and elevated renin-angiotensin-aldosterone (RAA) level. The variability of phenotypes is likely to be associated with the variety of SLC12A3 mutations. Methods In this study, we reported the clinical features and the genetic analysis of a GS family pedigree. Results We identified novel mutations of SLC12A3 , with c.433 C>T (p.Arg145Cys), c.1077 C>G (p.Asn359Lys), and c.1666 C>T (p.Pro556Ser). The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalcuria and kidney stone. The increased urinary calcium excretion made it confused to Bartter's syndrome (BS). The persistent renal potassium wasting associated renal tubular lesions finally affected urinary calcium reabsorption, leading to the increased calcium excretion. Genetic analysis revealed mutations of SLC12A3 with C433T (Arg145Cys, Het), C1077G (Asn359Lys, Het), and C1666T (Pro556Ser, Het). Those missense mutations led to the predicted amino acid change, caused differences of NCCT protein structures and function. One sister of the proband carried the same mutant sites, however, exhibited milder phenotypes including hypokalemia, hypomagnesemia, RAAS activation, but not elevated urinary calcium excretion. With administration of antisterone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained in normal ranges. Conclusions In this study, we identified the novel mutations of SLC12A3 and the varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of GS and its correlation with SLC12A3 mutations.