title: A role for CBS domain 2 in trafficking of chloride channel CLC-5.
abstract: CLC-5 is a member of the CLC family of voltage-gated chloride channels. Mutations disrupting CLC-5 lead to Dent's disease, an X-linked renal tubular disorder, characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal stones. Sequence analysis of CLC-5 reveals a 746 amino acid protein with an intracellular amino-terminus, transmembrane spanning domains, and two CBS domains within its intracellular carboxy-terminus. CBS domains have been implicated in intracellular targetting and trafficking as well as protein-protein interactions. We investigate subcellular localisation of three naturally occurring CLC-5 mutants which all lead to a truncated protein, disrupting the second CBS domain. These mutants are unable to traffic normally to acidic endosomes but are retained in perinuclear compartments, colocalising with the Golgi complex. This is the first identification of the cellular pathogenesis of CBS domain mutations of CLC-5.
authors.affiliation: School of Cell and Molecular Biosciences, University of Newcastle, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Carr
authors.forename: Nicholas
authors.initials: N
authors.lastname: Simmons
authors.forename: John
authors.initials: J
authors.lastname: Sayer
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D018118:Chloride Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003541:Cystathionine beta-Synthase / Q000737:chemistry; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D003541:Cystathionine beta-Synthase