title: Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1.
abstract: Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.
authors.affiliation: Department of Endocrinology & Metabolism, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sato
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakajima
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujieda
mesh_terms: D001477:Bartter Syndrome / Q000235:genetics* / Q000628:therapy; D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1
chemical_list: C578714:SLC12A1 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D004247:DNA