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Human Molecular Genetics Advance Access originally published online on February 24, 2006
Human Molecular Genetics 2006 15(7):1049-1058; doi:10.1093/hmg/ddl020
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Dominik Müller1,{dagger}, P. Jaya Kausalya2,{dagger}, Iwan C. Meij3 and Walter Hunziker2,*

1Department of Pediatric Nephrology and Center for Cardiovascular Research, Charité, Berlin, Germany, 2Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Singapore and 3Max-Delbrück-Center of Molecular Medicine, Berlin, Germany

* To whom correspondence should be addressed at: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore, Email: hunziker{at}imcb.a-star.edu.sg

Received November 8, 2005; Revised January 6, 2006; Accepted February 3, 2006

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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