August 2022 — Vol 142 No 8
A gain of function mutation of the E3 ubiquitin ligase KLHL24 results in increased proteasomal degradation of keratin 14 causing epidermolysis bullosa simplex. In addition to their skin disease, these patients with epidermolysis bullosa also develop alopecia. In their study, Cui et al (see pages 2079–2087) demonstrate in a knock-in mouse model that mutated KLHL24 leads to increased proteasomal degradation of keratin 15, resulting in a disruption of the structure of hair follicle stem cells. Long-term impairment of hair follicle stem cells leads to hair follicle degeneration and hair loss. In the same issue, Vermeer et al (see pages 2271–2274) report that in patients with gain-of-function mutations of KLHL24, degradation of K14 is most pronounced in fetal-stage undifferentiated keratinocytes. This explains why the skin manifestations of these patients are most pronounced after birth but improve over time.