title: Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome.
abstract: Gitelman's syndrome (GS) is an autosomal recessive disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria that has recently been reported to be linked to thiazide-sensitive Na-Cl cotransporter (TSC) gene mutations. In this study, possible mutations in the TSC gene of six Japanese patients clinically diagnosed with GS were investigated. Twenty-six exons encoding TSC were amplified by PCR and then completely sequenced by the direct sequencing method. Patient A showed a missense mutation of Arg 642 to Cys on the paternal allele and a missense mutation of Val 578 to Met and a 2-bp deletion (nucleotide 2543-2544) on the maternal allele. This deletion results in a frameshift that alters codon 837 to encode a stop signal rather than phenylalanine, and it is predicted to lead to loss of the latter half of the intracellular carboxy terminus. In the second family, two affected sisters, patients B and C, had a homozygous missense mutation of Thr 180 to Lys. Both of their parents, who are consanguineously married, have a heterozygous Thr180Lys mutation. Patient D has a homozygous mutation Thr180Lys, which is the same as the second family. Haplotype analysis indicates that patients B and C are not related to patient D. In patients E and F, we could identify only one mutant allele; Ala569Glu and Leu849His, respectively. All of the mutations identified are novel except for the Arg642Cys mutation, which has been found in a Japanese GS patient. Although further in vitro study is required to prove that the mutations are responsible for GS, it is possible that Thr180Lys and Arg642Cys mutations might be common mutations in Japanese GS.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Monkawa
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kurihara
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: D000328:Adult; D001477:Bartter Syndrome / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011955:Receptors, Drug / Q000235:genetics*; D012016:Reference Values; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor