{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T23:53:45Z","timestamp":1782604425754,"version":"3.54.5"},"reference-count":16,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hypokalemic metabolic tubulopathy, such as in Bartter syndrome and Gitelman syndrome, is caused by the dysfunction of renal electrolyte transporters. Despite advances in molecular genetics with regard to hypokalemic metabolic tubulopathy, recent reports have suggested that the phenotype-genotype correlation is still confusing, especially in classic Bartter and Gitelman syndromes. We report here two Japanese patients who suffered from clinically diagnosed classic Bartter syndrome but who presented hypocalciuria. Hypocalciuria is generally believed to be a pathognomonic finding of NCCT malfunction. To better understand the genotype-phenotype correlation in these two cases, we screened four renal electrolyte transporter genes [Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), Cl channel Kb (ClC-Kb), and Na-Cl cotransporter (NCCT)] by the PCR direct sequencing method. We identified three ClC-Kb allelic variants, including two new mutations (L27R and W610X in patient 1 and a G to C substitution of a 3\u2032 splice site of intron 2 and W610X in patient 2). We did not find any mutations in the other three genes. Our present data suggest that some ClC-Kb mutations may affect calcium handling in renal tubular cells.<\/jats:p>","DOI":"10.1210\/jc.2004-0775","type":"journal-article","created":{"date-parts":[[2004,11,5]],"date-time":"2004-11-05T01:39:05Z","timestamp":1099618745000},"page":"5847-5850","source":"Crossref","is-referenced-by-count":47,"title":["Novel Mutations of the Chloride Channel Kb Gene in Two Japanese Patients Clinically Diagnosed as Bartter Syndrome with Hypocalciuria"],"prefix":"10.1210","volume":"89","author":[{"given":"Shigeru","family":"Fukuyama","sequence":"first","affiliation":[{"name":"Department of Pediatrics (S.F., M.Hig., T.O.), Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0125, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misako","family":"Hiramatsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (M.Hir.), Nishibeppu National Hospital, Ohita 874-0833, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiro","family":"Akagi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (M.A.), Ohtemae Hospital, Osaka 540-0008, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutumi","family":"Higa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (S.F., M.Hig., T.O.), Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0125, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (S.F., M.Hig., T.O.), Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0125, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071616440052900_R1","first-page":"1045","article-title":"Hypokalemic tubular disorders: the hyperprostaglandin E syndrome and Gitelman-Bartter syndrome","author":"Seyberth","year":"1997","journal-title":"In: Daviclinical nephrology. 2nd ed. Oxford, UK: Oxford University Press;"},{"key":"2020071616440052900_R2","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/S0022-3476(85)80395-4","article-title":"Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome.","volume":"107","author":"Seyberth","year":"1985","journal-title":"J Pediatr"},{"key":"2020071616440052900_R3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/ng0696-183","article-title":"Bartter\u2019s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.","volume":"13","author":"Simon","year":"1996","journal-title":"Nat Genet"},{"key":"2020071616440052900_R4","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/ng1096-152","article-title":"Genetic heterogeneity of Bartter\u2019s syndrome revealed by mutations in the K+ channel, ROMK.","volume":"14","author":"Simon","year":"1996","journal-title":"Nat Genet"},{"key":"2020071616440052900_R5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ng1097-171","article-title":"Mutations in the chloride channel gene, CLCNKB, cause Bartter\u2019s syndrome type III.","volume":"17","author":"Simon","year":"1997","journal-title":"Nat Genet"},{"key":"2020071616440052900_R6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng0196-24","article-title":"Gitelman\u2019s variant of Bartter\u2019s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.","volume":"12","author":"Simon","year":"1996","journal-title":"Nat Genet"},{"key":"2020071616440052900_R7","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1046\/j.1523-1755.2003.00163.x","article-title":"Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis.","volume":"64","author":"Fukuyama","year":"2003","journal-title":"Kidney Int"},{"key":"2020071616440052900_R8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0002-9343(01)01086-5","article-title":"Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies.","volume":"112","author":"Peters","year":"2002","journal-title":"Am J Med"},{"key":"2020071616440052900_R9","doi-asserted-by":"crossref","first-page":"24261","DOI":"10.1016\/S0021-9258(19)51076-6","article-title":"Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel.","volume":"269","author":"Shuck","year":"1994","journal-title":"J Biol Chem"},{"key":"2020071616440052900_R10","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1681\/ASN.V1181449","article-title":"Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.","volume":"11","author":"Konrad","year":"2000","journal-title":"J Am Soc Nephrol"},{"key":"2020071616440052900_R11","doi-asserted-by":"crossref","first-page":"6943","DOI":"10.1073\/pnas.91.15.6943","article-title":"Two highly homologous members of the ClC chloride channel family in both rat and human kidney.","volume":"91","author":"Kieferle","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071616440052900_R12","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/415287a","article-title":"X-ray structure of a ClC chloride channel at 3.0 A\u030a reveals the molecular basis of anion selectivity.","volume":"415","author":"Dutzler","year":"2002","journal-title":"Nature"},{"key":"2020071616440052900_R13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1046\/j.1523-1755.2003.00730.x","article-title":"A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndrome.","volume":"63","author":"Zelikovic","year":"2003","journal-title":"Kidney Int"},{"key":"2020071616440052900_R14","doi-asserted-by":"crossref","first-page":"29150","DOI":"10.1074\/jbc.273.44.29150","article-title":"Phenotype resembling Gitelman\u2019s syndrome in mice lacking the apical Na+-Cl\u2212 cotransporter of the distal convoluted tubule.","volume":"30","author":"Schultheis","year":"1998","journal-title":"J Biol Chem"},{"key":"2020071616440052900_R15","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1681\/ASN.V15832","article-title":"Cellular actions of thiazide diuretics in the distal tubule.","volume":"1","author":"Stanton","year":"1990","journal-title":"J Am Soc Nephrol"},{"key":"2020071616440052900_R16","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1681\/ASN.V1271327","article-title":"Internal and cellular localization of CLC-K2 protein in the mouse kidney.","volume":"12","author":"Kobayashi","year":"2001","journal-title":"J Am Soc Nephrol"}],"container-title":["The Journal of Clinical Endocrinology &amp; 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