ADAM17 Variant Causes Hair Loss via Ubiquitin Ligase TRIM47 Mediated Degradation

The study identifies a dominant variant in the ADAM17 gene (p.D647N) as a cause of hypotrichosis with woolly hair. Using a knock-in mouse model, researchers observed that this mutation leads to hair follicle stem cell (HFSC) exhaustion and abnormal hair follicles, resulting in alopecia. Mechanistic studies showed that the ADAM17 variant increases its interaction with the E3 ubiquitin ligase TRIM47, enhancing ADAM17 protein degradation. This degradation disrupts the Notch signaling pathway, impairing HFSC activation, proliferation, and differentiation during hair follicle regeneration. Overexpression of NICD was able to rescue the proliferation defects in primary fibroblast cells caused by the ADAM17 variant.