Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Dale W. Laird

Abstract

Connexin 30 (Cx30), a member of the large gap junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigated four autosomal dominant Cx30 gene mutations linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild-type Cx30. The V37E mutant associated with keratitis-ichthyosis-deafness (KID) syndrome was retained in the endoplasmic reticulum (ER) and significantly induced unfolded protein response (UPR)-mediated apoptosis. The loss-of-function G59R mutant linked to Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus. Lastly, the Clouston syndrome-linked A88V mutant significantly induced apoptosis, primarily through an UPR-independent mechanism. Collectively, we discovered that four unique Cx30 mutants cause disease through different mechanisms, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.


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