Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage.

Joakim Klar,Maria Asif,Jens Schuster,Dorothee Günzel,Katrin Mäbert,Anja Fromm,Muhammad Tariq,Shahid M Baig,Jörg Piontek,Susanne Milatz,Ambrin Fatima,Tilman Breiderhoff,Niklas Dahl,Muhammad Jameel,Muhammad Sher

doi:10.1371/journal.pgen.1006897

Abstract

Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function.

Highlights

Epithelial and endothelial cells constitute sheets that divide organs into functional compartments
Claudins are tight junction proteins forming paracellular barriers that are critical for normal development and homeostasis
The tissue specific paracellular barrier properties are determined by the protein composition of tight junctions that regulates the permeability of solutes and water between different compartments of the body

Summary

Introduction

Epithelial and endothelial cells constitute sheets that divide organs into functional compartments. Homeostasis of different organ and body compartments are dependent on epithelial cells and their paracellular barrier that prevents solutes and water from leaking between the cells. The tissue specific paracellular barrier properties are determined by the protein composition of tight junctions (TJs) [1]. Some TJs form truly impermeable barriers whereas others contain paracellular channels for selective exchange of small ions between compartments. The selectivity is largely determined by the expression of specific members of the claudin protein family [2, 3]. The critical roles for claudin proteins in development and homeostasis are documented by mouse models as well as by some rare human diseases. Variants in the CLDN16 and CLDN19 genes are associated with hypomagnesemia, hypercalciuria and nephrocalcinosis (OMIM #248250 and OMIM #248190), CLDN14 mutations causes a form of autosomal recessive deafness (OMIM #614035) and CLDN1 mutations have been described in rare patients with ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC; OMIM#607626) [8,9,10,11,12]

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