Analysis Of The Function Of ADAM17 In IRhom2 Curly-Bare And Tylosis With Esophageal Cancer Mutant Mice

Tylosis with oesophageal cancer (TOC) is linked to mutations in iRhom2 (iR2), which regulates the metalloprotease ADAM17. In mice, a cytoplasmic deletion in iR2 causes severe alopecia and skin issues, while a knock-in TOC mutation results in milder hair abnormalities. These phenotypes are dependent on amphiregulin (Areg) and ADAM17, as reducing either gene's expression rescues the fur issues. Interestingly, iR1−/− iR2cub/cub mice survive without mature ADAM17, but iR2cub/cub Adam17−/− mice die perinatally, indicating that the iR2cub mutation requires ADAM17's presence but not its enzymatic activity. The iR2toc mutation selectively affects ADAM17's function without significantly reducing its levels. These findings enhance understanding of iR2's role and have potential implications for TOC treatment.