GoodenoughJCI2008 - Research article The Journal of...

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Unformatted text preview: Research article The Journal of Clinical Investigation      Volume 118      Number 2      February 2008  619 Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex Jianghui Hou, 1 Aparna Renigunta, 2 Martin Konrad, 3 Antonio S. Gomes, 1 Eveline E. Schneeberger, 4 David L. Paul, 5 Siegfried Waldegger, 2 and Daniel A. Goodenough 1 1 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. 2 University Children’s Hospital, Philipps-University Marburg, Marburg, Germany. 3 Department of Pediatrics, University of Münster, Münster, Germany. 4 Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA. 5 Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an inherited disorder caused by mutations in the genes encoding the TJ proteins claudin-16 (CLDN16) and CLDN19; however, the mecha- nisms underlying the roles of these claudins in mediating paracellular ion reabsorption in the kidney are not understood. Here we showed that in pig kidney epithelial cells, CLDN19 functioned as a Cl − blocker, whereas CLDN16 functioned as a Na + channel. Mutant forms of CLDN19 that are associated with FHHNC were unable to block Cl − permeation. Coexpression of CLDN16 and CLDN19 generated cation selectivity of the TJ in a synergistic manner, and CLDN16 and CLDN19 were observed to interact using several criteria. In addition, disruption of this interaction by introduction of FHHNC-causing mutant forms of either CLDN16 or CLDN19 abolished their synergistic effect. Our data show that CLDN16 interacts with CLDN19 and that their association confers a TJ with cation selectivity, suggesting a mechanism for the role of mutant forms of CLDN16 and CLDN19 in the development of FHHNC. Introduction The human renal disorder familial hypomagnesemia with hyper- calciuria and nephrocalcinosis (FHHNC; OMIM 248250) is char- acterized by progressive renal Mg 2+  and Ca 2+  wasting leading to  impaired renal function and chronic renal failure. FHHNC has  been genetically linked to mutations in the gene of claudin-16  (CLDN16, also known as paracellin-1) (1) and more recently  to CLDN19 (2). The claudins comprise a 22-gene family that  encodes essential structural proteins of the tight junction (TJ),  which are the principal regulators of paracellular permeability.  In vitro studies have shown that ion selectivity of the paracellular  conductance (reviewed in ref. 3) is a complex function of claudin  subtype and cellular context (4, 5)....
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GoodenoughJCI2008 - Research article The Journal of...

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