Abstract
BackgroundGitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity.MethodsIn this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome.ResultsThe proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges.ConclusionsIn this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.
Highlights
Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT)
Gitelman syndrome is associated with mutations of SLC12A3 gene, which locates on chromosome 16q13 and encodes the thiazidesensitive Na-Cl cotransporter (NCCT) of distal convoluted tubule (DCT) [2]
The fractional excretion rate of potassium (FEK%) was significantly increased to 30.5– 49.2%, suggesting that hypokalemia is resulted from renal potassium loss
Summary
Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Gitelman syndrome is characterized with clinical features including hypokalemia, renal potassium wasting, metabolic alkalosis, hypomagnesemia, hypocalciuria, and RAAS activation with normal blood pressure [1]. There are more than 400 varieties of SLC12A3 related to Gitelman syndrome have been reported [2,3,4,5]. Among those mutations, most are missense, deletion, insertion, and splice-site mutations [6]. Most SLC12A3 mutations in Gitelman syndrome are found as simple or complex heterozygous mutations, and few of them are homozygous [7]
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