Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome

Purpose:We aimed to identify the genetic cause to a clinicalsyndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal glanddysfunction, ichthyosis, and xerostomia (HELIXsyndrome), and to comprehensively delineate the phenotype.Methods:We performed homozygosity mapping, whole-genomesequencing, gene sequencing, expression studies, functional tests,protein bioinformatics, and histological characterization in twounrelated families with HELIX syndrome.Results:We identified biallelic missense mutations(c.386C>T,p.S131L and c.2T>C, p.M1T) inCLDN10Bin six patients fromtwo unrelated families.CLDN10Bencodes Claudin-10b, an integraltight junction (TJ) membrane-spanning protein expressed in thekidney, skin, and salivary glands. All patients had hypohidrosis,renal loss of NaCl with secondary hyperaldosteronismandhypokalemia, as well as hypolacrymia, ichthyosis, xerostomia,and severe enamel wear. Functional testingrevealed that patientshad a decreased NaCl absorption in the thick ascending limb of theloop of Henle and a severely decreased secretion of saliva. Bothmutations resulted in reduced or absent Claudin-10 at the plasmamembrane of epithelial cells.Conclusion:CLDN10mutations cause a dysfunction in TJs inseveral tissues and, subsequently, abnormalities in renal iontransport, ectodermalgland homeostasis, and epidermalintegrity.