Date: 12/08/2014

Keith Choate, MD, PhD Brittany Craiglow, MD

Many, if not most, human diseases have a genetic component. Thanks to advances in next-gen sequencing, a number of studies in recent years are beginning to unravel the role of de novo mutations — genetic variants that arise in a child but are not present in either parent, in human disease.

Drs. Keith Choate, Brittany Craiglow and their research team of the Yale University Disorders of Keratinization Project are employing the genetic tools to identify new genes causing ichthyosis and related skin types (aka”disorders of keratinization”).  With collaborators Drs. Amy Paller at Northwestern University, and Kim Morel and Christine Lauren at Columbia University, Dr. Choate’s group has discovered a new genetic cause of the disorder erythrokeratodermia variablis et progresiva (EKVP).  In three families, central to this discovery was finding novel dominant, de novo gene mutations in a gene called GJA1.  Mutations in GJA1 had previously been found to cause a very different disorder, oculodentodigital dysplasia (ODDD) which involves faulty development in the tissue of eyes, teeth, fingers and nervous system. The EKVP subjects showed none of these ODDD features.  GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein in the body, but the mutations found in EKVP appear to have a special role in the skin without effects on other organ systems.

 “These findings reveal a critical role for Cx43 in epidermal homeostasis, and provide evidence of organ-specific pathobiology resulting from different mutations within GJA1,” said Dr. Choate. “Especially important is the finding that this disorder has a relatively late age of onset, with completely normal skin until about 6 months of age.  If we can understand how these mutations cause skin disease, we are hopeful that we might be able to restore normal skin function for our patients.”

Other contributors to this work include Lynn Boyden,  Jing Zhou, and Rong-Hua Hu, all part of the Yale team.  The work was partly supported by the Yale Center for Mendelian Genomics.

Abstract available from Journal of Investigative Dermatology

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The Gene Discovery Program at Yale.

Check back for a more in-depth article regarding the findings, as well as the “process of discovery” from both the patient and clinician perspective.

Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia

Journal of Investigative Dermatology November (2014) | doi:10.1038/jid.2014.485

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