Mutation leading to progressive symmetric erythrokeratoderma identified

Keith Choate, MD. Photo courtesy Yale School of Medicine

New findings, published in PNAS, identify a gene variant that causes a rare form of ichthyosis, and suggest that epidermal growth factor receptor inhibitors, medications sometimes used to treat cancers, may be effective for treating the condition.

The study’s lead author, Keith Choate, MD, PhD, Aaron B. and Marguerite Lerner Professor and Chair of Dermatology and professor of genetics and pathology at the Yale School of Medicine in New Haven, Conn., collaborated with postdoctoral fellow Xingyuan Jiang, MD, MBBS, and MD/PhD student Ryland Mortlock to evaluate patients with a previously undescribed Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. The disorder features severely thickened, red, and scaly skin at sites of wound healing or repetitive movement, including on the face, genitals, flexural areas, and the palms and soles.

The team found that a recurrent mutation, arising uniquely in affected individuals but not present in their parents, caused the disorder. The affected gene, EMP2, encodes epithelial membrane protein 2, a cell surface tetraspan protein belonging to the growth-arrest-specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family.

EMP2 has previously been shown to directly associate with focal adhesion kinase (FAK), which links cell junction forces to signalling pathways relevant to proliferation, migration, and wound healing.

Researchers studied gene expression in affected skin using single-cell spatial transcriptomics. They discovered that pathways typically activated in proliferating cells in the basal layer of the skin, downstream of receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR), did not properly turn off during differentiation. This discovery provided rationale for treatment with erlotinib, an EGFR inhibitor indicated for non-small cell lung cancer and pancreatic cancer, which led to the resolution of skin disease at many sites.

“This study underscores the power of human genetics to reveal previously unknown functions for genes in the skin, setting the stage for development of new therapeutics,” said Dr. Choate, in a press release.