[PDF][PDF] A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting

D Müller, PJ Kausalya, F Claverie-Martin, IC Meij… - The American Journal of …, 2003 - cell.com
D Müller, PJ Kausalya, F Claverie-Martin, IC Meij, P Eggert, V Garcia-Nieto, W Hunziker
The American Journal of Human Genetics, 2003cell.com
Mutations in the gene coding for the renal tight junction protein claudin 16 cause familial
hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive
disorder of renal Ca 2+ and Mg 2+ handling that progressively leads to chronic renal failure,
with nephrolithiasis having been reported in heterozygous carriers. Screening a cohort of 11
families with idiopathic hypercalciuria identified a novel homozygous mutation in the claudin
16 gene in two families. In contrast to classical symptoms of familial hypomagnesemia with …
Mutations in the gene coding for the renal tight junction protein claudin 16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disorder of renal Ca2+ and Mg2+ handling that progressively leads to chronic renal failure, with nephrolithiasis having been reported in heterozygous carriers. Screening a cohort of 11 families with idiopathic hypercalciuria identified a novel homozygous mutation in the claudin 16 gene in two families. In contrast to classical symptoms of familial hypomagnesemia with hypercalciuria and nephrocalcinosis, the patients displayed serious but self-limiting childhood hypercalciuria with preserved glomerular filtration rate. The mutation results in inactivation of a PDZ-domain binding motif, thereby disabling the association of the tight junction scaffolding protein ZO-1 with claudin 16. In contrast to wild-type claudin 16, the mutant no longer localizes to tight junctions in kidney epithelial cells but instead accumulates in lysosomes. Thus, mutations at different intragenic sites in the claudin 16 gene may lead to particular clinical phenotypes with a distinct prognosis. Mutations in claudin 16 that affect interaction with ZO-1 lead to lysosomal mistargeting, providing—for the first time, to our knowledge—insight into the molecular mechanism of a disease-associated mutation in the claudin 16 gene.
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