Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage
2017
Claudinsconstitute the major component of
tight junctionsand 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 intoleranceand 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 glandsfrom 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
sweatsecretion 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 junctionstrand formation and altered cis-oligomer formation. These data suggest that
claudin-10b N48K causes
anhidrosisand 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 hyperparathyroidismand 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 junctionproteins and demonstrates a pivotal role for
claudin-10b in maintaining paracellular Na+ permeability for
sweatproduction and kidney function.
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