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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.

human molecular genetics online/human molecular genetics

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