Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage
Fig 1
The CLDN10b specific gene variant segregates anhidrosis and mild kidney failure.
(A) Pedigree of the consanguineous Pakistani family segregating anhidrosis and heat intolerance, alacrima, xerostomia, mild kidney failure and Mg2+ retention (black filled symbols). All affected individuals are homozygous for chromosome 13q32 marker alleles flanking the CLDN10 gene with the missense variant c.144C>G (black bars). (B) Body temperature measurements at rest over 25 min when exposed to 45°C and 45% humidity in affected (n = 2; black line) and age-matched controls (n = 3; grey line). The patients interrupted the study after 20 min due to distress. (C) The N48K variant is located within the 1st extracellular loop (ECL1) and results in the introduction of the positively charged Lysine in the claudin consensus sequence W- G/NLW-C-C (filled amino acids). The first 73 amino acids (black circles) are specific for the claudin-10b isoform encoded by exon 1b. Grey circles correspond to amino acids shared with the claudin-10a isoform. +/- indicate charged residues in the extracellular loops. ECL–extracellular loop. TM–Transmembrane segment. (D-E) Immunostaining of the secretory portion of sweat glands from a healthy control (D) and from the affected ind. 15 (E). In the control, claudin-10 (green) is predominantly found in the canaliculi, the cell peripheries and in membranes lining the lumen. Strong occludin staining (red) is found lining the main lumen of the sweat gland. In the patient, claudin-10 signal (green) is observed in membranes facing the lumen but shows a more even intracellular distribution without accumulation in canaliculi but in spots resembling vesicles. A strong occludin signal (red) is observed both in the canaliculi and in membranes lining the main lumen. Scale bars: 20μm.