Inhibition of mutant connexin channels in KID Syndrome (2022)
Thomas W. White
Department of Physiology & Biophysics
School of Medicine, StonyBrook University
FIRST is pleased to congratulate Thomas W. White PhD, Professor of Physiology & Biophysics at Stony Brook University School of Medicine for being selected as the 2022 FIRST Research Grant Recipient.
UPDATE June 2 2023: Progress report
The reviewers were supportive of the proposed antibody work but did not recommend full funding during this grant cycle. Thus, FIRST provided funding efforts at a reduced amount
($15,000) to conduct the innovative antibody approach.
We have completed the antibody studies in accordance with the reviewer’s recommendations. This work was published in EBioMedicine acknowledging the financial support of FIRST 1. A brief summary of the work follows. Mutations in connexin26 (Cx26, or GJB2) that increase hemichannel activity underlie the skin disease keratitis-ichthyosis-deafness syndrome (KID). For diseases like KID syndrome, there is no cure, there are limited options for palliation, and the combined impact of hearing loss, disfigurement, and blindness greatly diminishes the quality of life for the affected individuals who survive infancy. Cx26 mutations causing KID syndrome induce increased hemichannel activity as their main functional change, and specific monoclonal antibodies have been developed to block this acquired activity. We showed that the epidermal pathology can be alleviated in a mouse model that replicates the skin disease associated with human KID syndrome by systemic administration of a monoclonal antibody that blocks connexin hemichannels. These results confirmed the hypothesis that increased hemichannel activity is a significant contributor to epidermal pathology in KID syndrome, and further show the potential use of specific monoclonal antibodies to inhibit hemichannel activity as a new therapeutic intervention to treat this disease.
We have also studied a connexin43 (Cx43, or GJA1) mutation causing a familial connexinopathy exhibiting hypotrichosis with follicular keratosis and hyperostosis. This work was published in the International Journal of Molecular Sciences acknowledging the financial support of FIRST 2. A brief summary of the work follows. Mutations in the GJA1 gene that encodes Cx43 cause several rare genetic disorders, including diseases affecting the epidermis. We examined the in vitro functional consequences of a Cx43 mutation, Cx43-G38E, linked to a novel human phenotype of hypotrichosis, follicular keratosis and hyperostosis. We found that Cx43-G38E was efficiently translated and localized to gap junction plaques. Cx43-G38E formed functional gap junction channels with the same efficiency as wild-type Cx43, although voltage gating of the gap junction channels was altered. Notably, Cx43-G38E significantly increased membrane current flow through the formation of active hemichannels when compared to wild-type Cx43. These data demonstrate the association of increased hemichannel activity to a connexin mutation linked to a skeletal-cutaneous phenotype, suggesting that augmented hemi-channel activity could play a role in skin and skeletal disorders caused by human Cx43 mutations.
With the completion of these two studies, 97% of the original reduced budget has been spent. A balance of $491.55 remains. This will be used to partially support studies of a novel Cx26 mutation linked to skin disease that shows a phenotype that is acantholytic and displays desmosomal defects in the affected skin.
Progress report publication list:
1. Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice. Peres C, Sellitto C, Nardin C, Putti S, Orsini T, Di Pietro C, Marazziti D, Vitiello A, Calistri A, Rigamonti M, Scavizzi F, Raspa M, Zonta F, Yang G, White TW, Mammano F. EBioMedicine. 2023 Mar;89:104453. doi:
10.1016/j.ebiom.2023.104453. Epub 2023 Feb 1.
2. Increased Hemichannel Activity Displayed by a Connexin43 Mutation Causing a Familial Connexinopathy Exhibiting Hypotrichosis with Follicular Keratosis and Hyperostosis. Crouthamel OE, Li L, Dilluvio MT, White TW. Int J Mol Sci. 2023 Jan 22;24(3):2222. doi: 10.3390/ijms24032222.
UPDATE March 2023: Results from this work have been published. Read the article here.
Mutations in connexin26 (Cx26) that cause keratitis-ichthyosis-deafness (KID) syndrome have increased hemichannel activity. We will test inhibition of mutant hemichannels as a strategy to alleviate the skin pathology of KID syndrome in a mouse model.
To test inhibition of mutant connexin hemichannels as a new therapeutic approach in a mouse model that expresses the human Cx26-G45E KID syndrome mutation. These mice have increased hemichannel activity in keratinocytes. We hypothesize that inhibiting the acquired hemichannel activity will improve skin disease.
“I have studied connexin biology for 33 years employing a wide variety of electrophysiological, molecular biological, histological and genetic methodologies. I have had NIH grants from the National Eye Institute, National Institute of Arthritis and Musculoskeletal and Skin Disease, and the National Institute of Deafness and Other Communication Disorders, to study how connexins contribute to genetic diseases and normal development of the eye, skin, and ear. In our studies of mutations in connexin26 (Cx26 or GJB2) underlying syndromic and nonsyndromic forms of deafness, we have shown that total loss of Cx26 function is a common outcome in nonsydromic deafness. In addition, we showed that gain of function hemichannel activity was a common feature of keratitis-ichthyosis-deafness (KID) syndrome, and generated a mouse model that fully replicated the epidermal phenotype of KID syndrome patients. In this application, we will test inhibition of hemichannel activity in our mouse model as a novel therapeutic strategy to treat KID syndrome.”