title: Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing.
abstract: Dent's disease is an X-linked recessive disorder affecting the proximal tubules and is frequently associated with mutations in CLCN5, which encodes the electrogenic chloride-proton exchanger ClC-5. To better understand the functional consequences of CLCN5 mutations in this disease, we screened four newly identified missense mutations (G179D, S203L, G212A, L469P), one new nonsense mutation (R718X), and three known mutations (L200R, C219R, and C221R), in Xenopus laevis oocytes and HEK293 cells expressing either wild-type or mutant exchanger. A type-I mutant (G212A) trafficked normally to the cell surface and to early endosomes, underwent complex glycosylation at the cell surface like wild-type ClC-5, but exhibited significant reductions in outwardly rectifying ion currents. The type-II mutants (G179D, L200R, S203L, C219R, C221R, L469P, and R718X) were improperly N-glycosylated and were non-functional due to retention in the endoplasmic reticulum. Thus these mutations have distinct mechanisms by which they could impair ClC-5 function in Dent's disease.
authors: UPMC Université Paris 06, UMR 7134, Paris, France.
authors: Teddy
authors: T
authors: Grand
authors: David
authors: D
authors: Mordasini
authors: Sébastien
authors: S
authors: L'Hoste
authors: Thomas
authors: T
authors: Pennaforte
authors: Mathieu
authors: M
authors: Genete
authors: Marie-Jeanne
authors: MJ
authors: Biyeyeme
authors: Rosa
authors: R
authors: Vargas-Poussou
authors: Anne
authors: A
authors: Blanchard
authors: Jacques
authors: J
authors: Teulon
authors: Stéphane
authors: S
authors: Lourdel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D018389:Codon, Nonsense; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008564:Membrane Potentials; D008845:Microinjections; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012307:Risk Factors; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D002712:Chlorides; D018389:Codon, Nonsense