SLC12A3 – Gitelman Syndrome

Gitelman syndrome (GS; MONDO:0009904) is a recessively inherited salt-wasting tubulopathy characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. It results from biallelic inactivating mutations in the thiazide-sensitive Na–Cl cotransporter gene, SLC12A3 (HGNC:10912). Patients typically present in late childhood or adulthood with muscle weakness, tetany and secondary hyperreninemic hyperaldosteronism, yet blood pressure remains normal or low.

Genetic evidence is robust: over 300 distinct SLC12A3 variants have been reported in more than 500 unrelated GS probands (PMID:10616841). Variants span missense (e.g., c.539C>A (p.Thr180Lys)), nonsense, frameshift and splice–site changes, with reports of recurrent alleles (Thr180Lys in Japanese) and founder mutations (c.1196_1202dup7bp in Italians). Compound heterozygosity and homozygosity confirm autosomal recessive inheritance across diverse ethnic groups, and carrier frequency studies estimate a heterozygote rate of ~3% in some populations ([PMID:15198479]).

Segregation data support causality: multi-generation pedigrees, including a South African kindred with 5 affected individuals sharing compound heterozygous SLC12A3 alleles (PMID:28125972), and prematurely born twins demonstrating early hypokalemia at 3 weeks of age (PMID:20552229). In an Asian pedigree study, three homozygous and six carrier members exhibited genotype–phenotype correlations aligned with GS features. Together, these familial studies confirm segregation of variants with disease.

Functional assays in Xenopus oocytes and mammalian cells classify SLC12A3 mutations into trafficking-defective and intrinsic-activity-deficient classes. For example, class I mutants (G439S, T649R, G741R) fail to traffic to the cell surface, while class II mutants (L215P, F536L, R955Q) reach the membrane but exhibit reduced Na uptake (PMID:12039972). SPAK/WNK kinase studies further elucidate regulatory pathways, demonstrating that WNK4 mutations disrupt NCC inhibition and enhance cotransporter activity in PHAII, the phenotypic opposite of GS ([PMID:12515852]).

A minority of cases exhibit atypical presentations—normomagnesemia or normocalciuria—and up to 10% carry only one identifiable SLC12A3 allele, underscoring the need for functional and splicing analyses to confirm exon skipping or deep-intronic effects (PMID:19508680). No bona fide reports dispute the SLC12A3–GS association; rather, recognition of atypical biochemistry has refined diagnostic criteria.

Integration of genetic, segregation and functional data yields a Definitive gene–disease association. The breadth of variant spectrum, consistent autosomal recessive segregation and concordant loss-of-function studies provide the highest level of clinical validity. Clinically, SLC12A3 sequencing informs definitive diagnosis, guides electrolyte management and genetic counseling. Key take-home: SLC12A3 mutation analysis is essential for confirming Gitelman syndrome and tailoring lifelong electrolyte repletion.

References

• Journal of the American Society of Nephrology • 2000 • Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome PMID:10616841
• Journal of the American Society of Nephrology • 2002 • Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman's syndrome PMID:12039972
• Pediatric Nephrology • 2010 • Early appearance of hypokalemia in Gitelman syndrome PMID:20552229
• BMC Nephrology • 2017 • Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings PMID:28125972
• Hypertension Research • 2004 • A high prevalence of Gitelman's syndrome mutations in Japanese PMID:15198479
• Clinical Endocrinology • 2010 • Problems in diagnosing atypical Gitelman's syndrome presenting with normomagnesaemia PMID:19508680

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