ABSTRACT
Claudin-14 protein plays an essential role in regulating calcium ions in the kidney and ear. Two phenotypes, hearing loss and kidney stones, were reportedly associated with variations in the CLDN14 gene. This study aimed to understand CLDN14 mutations' contribution to hearing loss and renal stone formation in a Pakistani cohort. We analyzed CLDN14 sequence variations in 100 patients, along with healthy individuals, to assess whether specific polymorphisms were associated with the disease. Also, we performed an in silico analysis using a mutation database and protein annotation. The rs219779's genotype CT (p = 0.0020) and rs219780's genotype AG (p = 0.0012) were significantly associated with kidney stones. We also found that a novel haplotype, "TA" associated with kidney stone formation, has moderate linkage disequilibrium. The TA haplotype was significantly correlated with a kidney stone risk formation of 3.76-fold (OR (CI 95%) = 3.76 (1.83-7.72)) and p = 0.0016 compared to other haplotypes. In silico analysis revealed that mutations associated with hearing loss were not correlated with renal stone formation but affected claudin-14 protein stability. We structurally mapped a novel TA haplotype of CLDN14 that, based on our analysis, likely contributes to the pathogenesis of renal stones.
