Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/provides a new model to study atopic dermatitis.

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.