Gain of function p.E138A alteration in Card14 leads to psoriasiform skin inflammation and implicates genetic modifiers in disease severity.

Gain of function p.E138A alteration in Card14 leads to psoriasiform skin inflammation and implicates genetic modifiers in disease severity. Exp Mol Pathol. 2019 Jul 16;:104286 Authors: Sundberg JP, Pratt CH, Silva KA, Kennedy VE, Qin W, Stearns TM, Frost J, Sundberg BA, Bowcock AM Abstract Psoriasis (PS) is a common inflammatory and incurable skin disease affecting 2-3% of the human population. Although genome-wide association studies implicate more than 60 loci, the full complement of genetic factors leading to disease is not known. Rare, highly penetrant, gain-of-function, dominantly acting mutations within the human caspase recruitment domain family, member 14 (CARD14) gene lead to the development of PS and psoriatic arthritis (PSA) (a familial p.G117S and de-novo p.E138A alteration). These residues are conserved in mouse and orthologous Knock-In (KI) mutations within Card14 were created. The Card14tm.1.1Sun allele (G117S) resulted in no clinically or histologically evident phenotype of the skin or joints in young adult or old mice. However, mice carrying the Card14tm2.1Sun mutant allele (E138A) were runted and developed thick, white, scaly skin soon after birth, dying within two weeks or less. The skin hyperplasia and inflammation was remarkable similarity to human PS at the clinical, histological, and transcriptomic levels. For example, the skin was markedly acanthotic and exhibited orthokeratotic hyperkeratosis with minimal inf...
Source: Experimental and Molecular Pathology - Category: Pathology Authors: Tags: Exp Mol Pathol Source Type: research