Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly

Formation of claudin-10 based tight junctions (TJs) is paramount to paracellular Na+ transport in multiple epithelia. Sequence variants in CLDN10 have been linked to HELIX syndrome, a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary, sweat, and lacrimal glands. Here, we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10. In addition to hypohidrosis (H), electrolyte (E) imbalance with impaired urine concentrating abil-ity, and hypolacrimia (L), phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis (I) nor xerostomia (X). Employing cellular TJ reconstitution assays, we demonstrate perturbation of cis- and trans-interactions between mutant claudin-10 proteins. Ultrastructures of reconstituted TJ strands show disturbed conti-nuity and reduced abundance in the mutant case. Throughout, both major isoforms, claudin-10a and claudin-10b, are differentially affected with claudin-10b showing more severe molec-ular alterations. However, expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity, indicating that aberrant claudin-10 is generally capable of forming functional paracellular channels. Thus, mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly. Additional ex vivo investiga-tions indicate their insertion into TJs to occur in a tissue-specific manner.Copyright (C) 2021, Chongqing Medical University. Production and hosting by Elsevier B.V.

Automated summary

This study investigated the molecular basis and phenotypic consequences of a CLDN10 gene variant, which disrupts the assembly of tight junction (TJ) strands. The mutant proteins compromised the function of TJ and exhibited tissue-specific insertion into TJs.