title: A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting.
abstract: 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 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.
authors: Charité Children's Hospital, Department of Pediatric Nephrology, Berlin, Germany. dominik.mueller@charite.de
authors: Dominik
authors: D
authors: Müller
authors: P Jaya
authors: PJ
authors: Kausalya
authors: Felix
authors: F
authors: Claverie-Martin
authors: Iwan C
authors: IC
authors: Meij
authors: Paul
authors: P
authors: Eggert
authors: Victor
authors: V
authors: Garcia-Nieto
authors: Walter
authors: W
authors: Hunziker
mesh_terms: D001345:Autoradiography; D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D002478:Cells, Cultured; D057167:Claudins; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010375:Pedigree; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D062826:Zonula Occludens-1 Protein
chemical_list: D057167:Claudins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C502010:claudin 16; D002118:Calcium