title: Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome.
abstract: Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jae Wook
authors.identifier: 0000-0003-0120-8164
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Hallym University Hangang Sacred Heart Hospital, Seoul, Korea.
authors.forename: Jeonghwan
authors.identifier: 0000-0003-3199-635X
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea.
authors.forename: Nam Ju
authors.identifier: 0000-0003-3721-4830
authors.initials: NJ
authors.lastname: Heo
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.; Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea.; Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hae Il
authors.identifier: 0000-0001-7556-1265
authors.initials: HI
authors.lastname: Cheong
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jin Suk
authors.identifier: 0000-0001-6892-5518
authors.initials: JS
authors.lastname: Han
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001477:Bartter Syndrome / Q000235:genetics / Q000473:pathology; D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D053579:Gitelman Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007008:Hypokalemia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics; D055815:Young Adult
chemical_list: C412733:CLCNKB protein, human; D018118:Chloride Channels; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3
keywords: Bartter Syndrome; CLCNKB; Gitelman Syndrome; SLC12A3; Salt-losing Tubulopathy