Iris Schrijver, M.D.

The Research

Stanford University School of Medicine

The functional impact of single and dual expression of GJB2 missense variants V271 and E114G: An exploration of pathogenic effects on hearing

It is difficult to predict the consequences of DNA alterations that result in the replacement of one protein building block by another. Yet, an important aspect of genetic testing is to predict whether a DNA change is harmful or not. With this project, we will solve this dilemma for two relatively common variants in the connexin 26 gene. Interestingly, it appears that these two variants do not contribute to hearing loss when opposite of a disease causing change separately, but when they occur together opposite such a change, there is hearing loss as if these changes have an additive deleterious effect. By using techniques in which we are experienced, we plan to continue our research in hearing loss and directly observe whether and how these variants affect the connexin 26 protein functions within the cell. We will determine the effect on the amount of connexin 26 proteins, on localization and transport within the cell, and on function by establishing whether the essential communication channels between cells are still formed. This work will enable the correct clinical interpretation of these commonly observed changes, and can help begin to link DNA changes to protein effects and clinical symptoms in patients with hearing loss.