RHBDF2 Gene: Function, Mutations, and Associated Diseases

RHBDF2 encodes iRhom2, a catalytically inactive rhomboid-like protein that functions as a crucial regulator of the metalloprotease ADAM17 (TACE). iRhom2 is required for the maturation, trafficking, and activity of ADAM17, which mediates the shedding of membrane-bound substrates including pro-TNFα, EGFR ligands, and other cytokines. Gain-of-function mutations in RHBDF2 cause tylosis with esophageal cancer (TOC), a syndrome characterized by palmoplantar keratoderma and high risk of esophageal squamous cell carcinoma. The gene is also implicated in inflammatory and immune responses.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• ADAM17-mediated shedding of EGFR ligands (Reactome: R-HSA-1227986)

• TNFα signaling (Reactome: R-HSA-75893)

• Interleukin-1 processing (Reactome: R-HSA-448424)

iRhom2 is a 7-transmembrane domain protein localized to the endoplasmic reticulum and Golgi. It lacks protease activity due to the absence of a catalytic serine residue but serves as an essential cofactor for ADAM17. iRhom2 binds ADAM17 in the ER, facilitates its exit from the ER, and promotes its maturation and trafficking to the cell surface. It also regulates the phorbol ester-stimulated shedding of ADAM17 substrates. The protein is highly expressed in keratinocytes, spleen, and lung, and its gain-of-function mutations are linked to familial tylosis and esophageal cancer.