title: Disease-causing dysfunctions of barttin in Bartter syndrome type IV.
abstract: Bartter syndrome type IV is an inherited human condition characterized by severe renal salt wasting and sensorineural deafness. The causal gene, BSND, encodes barttin, an accessory subunit of chloride channels located in the kidney and inner ear. Barttin modulates the stability, cell surface localization, and function of ClC-K channels; distinct mutations cause phenotypes of varying severity. For definition of the molecular basis of this diversity, the functional consequences of six disease-causing mutations (R8L, R8W, G10S, Q32X, G47R, and E88X) on ClC-K channel properties were studied by heterologous expression in renal cell lines, electrophysiology, confocal imaging, and biochemical analysis. Three missense mutations (R8L, R8W, and G10S) eliminated the function of ClC-K/barttin channels but did not prevent the insertion of the channels into the surface membrane. Another mutant that produces a mild renal phenotype (G47R) was capable of performing all functions of wild-type barttin but bound to ClC-K channels less effectively. The nonsense mutation E88X affected epithelial sorting, leading to equal amounts of barttin inserting into the basolateral and apical membranes, contrasting with the preferential apical insertion of wild-type barttin. Last, the nonsense mutation Q32X allowed barttin to associate with ClC-K channels but prevented surface membrane insertion and channel activation. These results demonstrate that Bartter syndrome type IV can be caused by various derangements in the function of barttin, likely contributing to the diversity of observed phenotypes.
authors.affiliation: Institut für Neurophysiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Audrey G H
authors.initials: AG
authors.lastname: Janssen
authors.forename: Ute
authors.initials: U
authors.lastname: Scholl
authors.forename: Constanze
authors.initials: C
authors.lastname: Domeyer
authors.forename: Doreen
authors.initials: D
authors.lastname: Nothmann
authors.forename: Ariane
authors.initials: A
authors.lastname: Leinenweber
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
mesh_terms: D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics*; D002460:Cell Line; D018118:Chloride Channels / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D018389:Codon, Nonsense; D004285:Dogs; D006031:Glycosylation; D006801:Humans; D015640:Ion Channel Gating; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: C440005:BSND protein, human; C489932:CLCNKA protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; D018389:Codon, Nonsense
references.citation: Brain Res. 2001 Sep 28;914(1-2):196-203
references.pmid: 11578612
references.citation: Biotechniques. 1994 Nov;17(5):876-81
references.pmid: 7840967
references.citation: Nature. 2001 Nov 29;414(6863):558-61
references.pmid: 11734858
references.citation: Am J Med. 1962 Dec;33:811-28
references.pmid: 13969763
references.citation: Philos Trans R Soc Lond B Biol Sci. 1982 Dec 1;299(1097):401-11
references.pmid: 6130538
references.citation: Biophys J. 2003 Apr;84(4):2306-18
references.pmid: 12668439
references.citation: J Biol Chem. 2004 Mar 26;279(13):13140-7
references.pmid: 14718533
references.citation: Annu Rev Physiol. 2005;67:759-78
references.pmid: 15709977
references.citation: Nature. 2002 Jan 17;415(6869):287-94
references.pmid: 11796999
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6943-7
references.pmid: 8041726
references.citation: J Physiol. 1980 Oct;307:97-129
references.pmid: 6259340
references.citation: Histochem Cell Biol. 2003 Jun;119(6):485-93
references.pmid: 12761627
references.citation: Curr Opin Nephrol Hypertens. 1998 Jan;7(1):43-7
references.pmid: 9442362
references.citation: Curr Opin Nephrol Hypertens. 2003 Sep;12(5):527-32
references.pmid: 12920401
references.citation: J Biol Chem. 2004 Sep 17;279(38):39505-12
references.pmid: 15265858
references.citation: J Gen Physiol. 1997 Jan;109(1):93-104
references.pmid: 8997668
references.citation: Pflugers Arch. 2002 Jun;444(3):411-8
references.pmid: 12111250
references.citation: Pediatrics. 2001 Jul;108(1):E5
references.pmid: 11433084
references.citation: Nat Genet. 2001 Nov;29(3):310-4
references.pmid: 11687798
references.citation: J Clin Endocrinol Metab. 2003 Feb;88(2):781-6
references.pmid: 12574213
references.citation: Methods Enzymol. 1998;296:307-18
references.pmid: 9779457
references.citation: Pediatr Nephrol. 2006 May;21(5):643-8
references.pmid: 16572343
references.citation: Pediatr Nephrol. 2006 Jul;21(7):1056-7
references.pmid: 16773427
references.citation: J Neurosci. 2002 Dec 15;22(24):10643-52
references.pmid: 12486157
references.citation: Nephrol Dial Transplant. 2007 Jan;22(1):288-9
references.pmid: 16935888
references.citation: Pediatrics. 2003 Sep;112(3 Pt 1):628-33
references.pmid: 12949294
references.citation: J Biol Chem. 1993 Feb 25;268(6):3821-4
references.pmid: 7680033
references.citation: Pediatr Nephrol. 2006 Feb;21(2):190-3
references.pmid: 16328537
references.citation: Am J Med Genet. 1995 Dec 4;59(4):454-9
references.pmid: 8585565
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11411-6
references.pmid: 16849430
references.citation: J Clin Invest. 1995 Jan;95(1):104-13
references.pmid: 7814604