Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene

Abstract

GJB2 alleles containing two cis mutations have been rarely found in non-syndromic hearing loss. Herein, we present a Korean patient with non-syndromic hearing loss caused by the R75Q cis mutation with V37I, which arose de novo in the father and was inherited by the patient. Biochemical coupling and hemichannel permeability assays were performed after molecular cloning and transfection of HEK293T cells. Student's t-tests or analysis of variance followed by Tukey's multiple comparison test was used as statistical analysis. Biochemical coupling was significantly reduced in connexin 26 (Cx26)-R75Q- and Cx26-V37I-transfected cells, with greater extent in Cx26-R75Q and Cx26-R75Q+V37I cells. Interestingly, our patient and his father with the mutations had more residual hearing compared with patients with the dominant mutation alone. Although the difference in hemichannel activity between R75Q alone and R75Q in combination with V37I failed to reach significance, it is of note that there is a possibility that V37I located upstream of R75Q might have the ability to ameliorate R75Q expression. Our study emphasizes the importance of cis mutations with R75Q, as the gene effect of R75Q can be modulated depending on the type of additional mutation.

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

“…Similarly, Xenopus oocytes injected with mRNA encoding p.Val37Ile showed no conductance above background, and co-injection of p.Val37Ile variant connexin 26 with wild-type connexin 26, connexin 30, or connexin 31 showed reduced conductance 19,28 . Propidium iodide dye transfer was impaired in GJB2 c.109G>A transfected HEK293T cells 29 . Homozygous knock-in mouse model of c.109G>A in Gjb2 was reported to have progressive mild hearing loss, more pronounced at higher sound frequencies 30 .…”

Consensus interpretation of the Met34Thr and Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

“…Similarly, Xenopus oocytes injected with mRNA encoding Val37Ile showed no conductance above background, and co-injection of Val37Ile variant connexin 26 with wild-type connexin 26, connexin 30, or connexin 31 showed reduced conductance 19, 28 . Propidium iodide dye transfer was impaired in GJB2 c.109G>A transfected HEK293T cells 29 . Homozygous knock-in mouse model of c.109G>A in Gjb2 was reported to have progressive mild hearing loss, more pronounced at higher frequencies 30 .…”

Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation

“…In vitro studies found that p.V37I mutation only partially reduced the permeability of GJs and dysfunctional hemichannels [23, 24]. In other forms of Gjb2 mutations, EP changes were found to be associated with hearing losses [25].…”