title: Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome.
abstract: Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred.
authors.affiliation: Department of Pediatrics, San Leopoldo Mandic Hospital, Merate, and Department of Pediatrics and Neonatology, University of Milan, Italy. abettinelli@ospedale.Lecco.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Bettinelli
authors.forename: Nicolò
authors.initials: N
authors.lastname: Borsa
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Syrén
authors.forename: Camilla
authors.initials: C
authors.lastname: Mattiello
authors.forename: Domenico
authors.initials: D
authors.lastname: Coviello
authors.forename: Alberto
authors.initials: A
authors.lastname: Edefonti
authors.forename: Marisa
authors.initials: M
authors.lastname: Giani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Travi
authors.forename: Silvana
authors.initials: S
authors.lastname: Tedeschi
mesh_terms: D000328:Adult; D027321:Anion Transport Proteins / Q000235:genetics*; D001477:Bartter Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011955:Receptors, Drug / Q000235:genetics*; D035781:Siblings; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics*
chemical_list: D027321:Anion Transport Proteins; C412733:CLCNKB protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters