title: Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain.
abstract: Gitelman syndrome (familial hypokalemia-hypomagnesemia syndrome) is an autosomal recessive inherited renal disorder characterized by defective tubular reabsorption of magnesium and potassium. In this study a group of 18 unrelated and 2 related Gitelman patients, collected from six different countries have been screened for mutations in the human thiazide-sensitive sodium-chloride cotransporter (SLC12A3) gene. Fourteen novel SLC12A3 mutations are presented along with six mutations described earlier, and three neutral polymorphisms. Among the tested patients are two who carry a total of three heterozygous SLC12A3 mutations. Two-thirds of the total number of mutant SLC12A3 alleles are amino acid substitutions. Most SLC12A3 gene mutations, 14 out of a total of 20, are localized at the intracellular carboxy-terminal domain of the NCCT protein. The pathogenicity of individual SLC12A3 mutations is based upon their predicted effect on SLC12A3 protein, and segregation in family members. Evolutionary conservation of substituted amino acid residues and their frequency in control chromosomes is presented. Identical mutations have been found in Gitelman families from different geographical origin, suggesting ancient mutations originating from a common ancestor. As yet, we have not found any evidence for a possible genotype-phenotype correlation.
authors.affiliation: Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
authors.forename: H H
authors.initials: HH
authors.lastname: Lemmink
authors.forename: N V
authors.initials: NV
authors.lastname: Knoers
authors.forename: L
authors.initials: L
authors.lastname: Károlyi
authors.forename: H
authors.initials: H
authors.lastname: van Dijk
authors.forename: P
authors.initials: P
authors.lastname: Niaudet
authors.forename: C
authors.initials: C
authors.lastname: Antignac
authors.forename: L M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: P R
authors.initials: PR
authors.lastname: Goodyer
authors.forename: J C
authors.initials: JC
authors.lastname: Carel
authors.forename: A
authors.initials: A
authors.lastname: Hermes
authors.forename: H W
authors.initials: HW
authors.lastname: Seyberth
authors.forename: L A
authors.initials: LA
authors.lastname: Monnens
authors.forename: L P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D000595:Amino Acid Sequence; D001581:Benzothiadiazines; D002352:Carrier Proteins / Q000235:genetics*; D004232:Diuretics; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008274:Magnesium / Q000097:blood*; D008969:Molecular Sequence Data; D009154:Mutation; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D049992:Sodium Chloride Symporters; D027981:Symporters; D013577:Syndrome
chemical_list: D001581:Benzothiadiazines; D002352:Carrier Proteins; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters; D027981:Symporters; D008274:Magnesium