Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

ABSTRACT

In humans, gain-of-function (GOF) mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG) secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis.

Abstract

Summary: Gain-of-function mutations in RHBDF2 cause tylosis, a skin disease characterized by hyperproliferation of keratinocytes. We generated mice carrying the human tylosis disease mutation p.P189L and show that enhanced amphiregulin secretion underlies tylosis.