Identifying a hyperkeratosis signature in autosomal recessive congenital Ichthyosis: Mdm2 inhibition prevents hyperkeratosis in a rat ARCI model

摘要

Autosomal recessive congenital ichthyo-sis (ARCI) is a Mendelian disorder of keratinization. LI patients are born as erythrodermic "collodion" babies but soon become covered with scales. The most commonly mutated genes in ARCI are Transglutaminase 1, Ichthyin, and the Arachidonate Lipoxygenases 12b and 3 (Russell et al., 1995; Jobard ef al., 2002; Fischer, 2009). Hyper-keratosis (scaling) is a cardinal feature of disorders of keratinization, which are characterized by abnormal barrier function. For example, Tgm1-null mice die perinatally because of transepi-dermal water loss after birth, but when this skin is grafted onto nude mice, they form scales similar to ARCI patients (Kuramoto ef al., 2002). The epidermis is hyperproliferative, produces increased non-polar lipid, and the cornified layer is thickened. This scaling is the principle phenotype in ARCI patients, and the time taken to remove scale significantly affects their quality of life.