394 Card14 knockin mouse model of psoriasis and psoriatic arthritis

Abstract

Despite intensive efforts there are still no good mouse models for psoriasis (Ps) and psoriatic arthritis (PsA). Although this partly reflects the differences between human and mouse skin, it is also because no bona-fide targets have been identified for genetic manipulation. The Bowcock lab identified gain-of-function, dominantly acting mutations, within CARD14 in human psoriasis patients that lead to Mendelian forms of Ps and PsA. CARD14 is expressed in keratinocytes and some immune cells and Ps/Psa associated mutations enhance NFKB activation. This suggests that these alterations in mice should lead to phenotypes that are similar to those seen in humans. We hypothesized that the G117S mutation would lead to inflammation of the skin and joints resembling Ps and PsA and that an E138A mutation would lead to a severe skin inflammation, similar to the child with pustular psoriasis in whom this mutation was first detected. Knockin mutations revealed clinically normal mice with the G117S mutation (B6N;129S4-Card14 tm1.1Sun ). Mutations in E138A (Card14 tm2.1Sun ) resulted in mice with thick scaly skin that died within the first week of life due to atrial septal defects in the heart. A subline was established that did survive to over 300 days of age with psoriasiform dermatitis but without pustules, possibly due to the high health status of the colonies. Crosses with other strains resulted in stable stocks on an FVB/NJ cross but not with C3H/HeJ, CBA/J, or 129S1/SvlmJ. These results verify that the E138A mutation has a potential role in epidermal hyperplasia and that its expression is under regulation of major modifier genes yet to be determined.