A recurrent de novo damaging variant in EMP2 causes progressive symmetric erythrokeratoderma
成果类型：
Article
署名作者：
Jiang, Xingyuan; Mortlock, Ryland D.; Pironon, Nathalie; Zhou, Jing; Hu, Ronghua; Liu, William; Acosta, Agustina; Shwayder, Tor A.; Hovnanian, Alain; Lifton, Richard P.; Choate, Keith A.
署名单位：
Yale University; Yale University; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Henry Ford Health System; Henry Ford Hospital; Rockefeller University; Yale University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-13543
DOI：
10.1073/pnas.2509896122
发表日期：
2025-08-12
关键词：
membrane-protein 2
epidermal-growth-factor
mutations
expression
gene
fak
differentiation
activation
variabilis
sequence
摘要：
Genetic investigation in Mendelian skin disorders featuring generalized or localized skin scaling and redness, known as the ichthyoses, has revealed novel pathways relevant to epidermal integrity, barrier function, and desquamation. Here, we show that a recurrent de novo missense variant in EMP2 (epithelial membrane protein 2), which encodes a cell surface tetraspan protein in the growth- arrest specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family, is associated with a Mendelian skin 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. EMP2 has previously been shown to directly associate with focal adhesion kinase, which links cell junction forces to signaling pathways relevant to proliferation, migration, and wound healing. Using single- cell spatial transcriptomics in affected tissue, we found ectopic suprabasal activation of signaling pathways downstream of receptor tyrosine kinases including epidermal growth the key role of EMP2 in epidermal differentiation and proliferation.