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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail

Item Type:Article
Title:Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail
Creators Name:Mueller, D. and Kausalya, P.J. and Meij, I.C. and Hunziker, W.
Abstract:Mutations in the gene for Claudin-16 (CLDN16) are linked to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a renal Mg2+ and Ca2+ wasting disorder that leads to progressive kidney failure. More than 20 mutations have been identified in CLDN16, which, with a single exception, affect one of two extracellular loops or one of four transmembrane domains of the encoded protein. Here, we describe a novel missense mutation, Cldn16 L203X, which deletes the entire C-terminal cytosolic domain of the protein. Surface expression of Cldn16 L203X is strongly reduced and the protein is instead found in the endoplasmic reticulum (ER) and lysosomes. ER-retained Cldn16 L203X is subject to proteasomal degradation. Cldn16 L203X present in lysosomes reaches this compartment following transport to the plasma membrane and endocytosis. Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X. Thus, endocytosis inhibitors may provide a novel therapeutic approach for FHHNC patients carrying particular Cldn16 mutations.
Keywords:Amino Acid Sequence, Biological Transport, Calcium Metabolism Disorders, Clathrin, Claudins, Cultured Cells, Endocytosis, Endoplasmic Reticulum, Fluorescent Antibody Technique, HeLa Cells, Homozygote, Kidney, Lysosomes, Magnesium Deficiency, Membrane Proteins, Molecular Sequence Data, Mutation, Nephrocalcinosis, Phenotype, Proteasome Endopeptidase Complex, Transfection, Animals, Dogs
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:15
Number:7
Page Range:1049-1058
Date:1 April 2006
Official Publication:https://doi.org/10.1093/hmg/ddl020
PubMed:View item in PubMed

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