Structural basis for pathogenic variants of GJB2 and hearing levels of patients with hearing loss

Abstract

Abstract OBJECTIVES The crystal structure of the six protomers of gap junction protein beta 2 (GJB2) enables prediction of the effect(s) of an amino acid substitution, thereby facilitating investigation of molecular pathogenesis of missense variants of GJB2. This study mainly focused on R143W variant that causes hearing loss, and investigated the relationship between amino acid substitution and 3-D structural changes in GJB2.METHODS The R143W and structurally related variants of GJB2 were modeled using the crystal structure of GJB2 as a template. Patients with nonsyndromic hearing loss who appeared to have two GJB2 pathogenic variants, including the R143W variant, were investigated.RESULTS The predicted structure demonstrated that the hydrogen bond between R143 and N206 was important for the stability of the protomer structure. Also, R143W related N206S and N206T variants showed loss of the hydrogen bond.CONCLUSION Investigation of the genotypes and clinical data in patients carrying the R143W variant on an allele indicated that severity of hearing loss depends largely on the levels of dysfunction of the pathogenic variant on the allele, whereas a patient with the homozygous R143W variant demonstrated profound hearing loss. We concluded that the R143W variant causes structural destabilization of protein of GJB2.