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

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 inflammation and no pustules and transcripts affecting critical pathways of epidermal differentiation and components of the IL17 axis (IL23, IL17A, IL17C, TNF and IL22) were altered. Similar changes were seen in a set of orthologous microRNAs previously associated with PS suggesting conservation across species. Crossing the Card14tm2.1Sun/WT mice to C57BL/6NJ, FVB/NJ, CBA/J, C3H/HeJ, and 129S1/SvImJ generated progeny with epidermal acanthosis and marked orthokeratotic hyperkeratosis regardless of the hybrid strain. Of these hybrid lines, only the FVB;B6N(129S4) mice survived to 250 days of age or older and has led to recombinant inbred lines homozygous for Card14E138A that are fecund and have scaly skin disease. This implicates that modifiers of PS severity exist in mice, as in the familial forms of the disease in humans.

journal_name

Exp Mol Pathol

journal_title

Experimental and molecular pathology

authors

Sundberg JP,Pratt CH,Silva KA,Kennedy VE,Qin W,Stearns TM,Frost J,Sundberg BA,Bowcock AM

doi

10.1016/j.yexmp.2019.104286

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

104286

eissn

0014-4800

issn

1096-0945

pii

S0014-4800(19)30174-1

journal_volume

110

pub_type

杂志文章

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