The Jackson Laboratory, Bar Harbor, ME, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Exp Mol Pathol. 2019 Oct;110:104286. doi: 10.1016/j.yexmp.2019.104286. Epub 2019 Jul 16.
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 Card14 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 Card14 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 Card14/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 Card14 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.
银屑病（PS）是一种常见的炎症性和不可治愈的皮肤病，影响了人类人口的 2-3%。尽管全基因组关联研究表明有超过 60 个位点，但导致疾病的全部遗传因素尚不清楚。在人类半胱氨酸天冬氨酸蛋白酶募集域家族成员 14（CARD14）基因中，罕见的、高外显率、功能获得、显性作用的突变导致 PS 和银屑病关节炎（PSA）的发生（家族性 p.G117S 和从头发生的 p.E138A 改变）。这些残基在小鼠中是保守的，并且在同源的敲入（KI）突变中创建了同源的 Knock-In（KI）突变。Card14 等位基因（G117S）在幼鼠或老年鼠的皮肤或关节中没有临床或组织学上明显的表型。然而，携带 Card14 突变等位基因（E138A）的小鼠出生后很快就会变得矮小，皮肤变得又厚又白，有鳞片状，在两周或更短的时间内死亡。皮肤过度增生和炎症在临床、组织学和转录组学水平上与人类 PS 非常相似。例如，皮肤明显棘皮增生，表现为正角化过度角化，炎症最小，无脓疱，影响表皮分化关键途径和 IL17 轴成分的转录本（IL23、IL17A、IL17C、TNF 和 IL22）发生改变。以前与 PS 相关的一组同源 microRNAs 也出现了类似的变化，表明在物种间存在保守性。将 Card14/WT 小鼠与 C57BL/6NJ、FVB/NJ、CBA/J、C3H/HeJ 和 129S1/SvImJ 杂交，产生了具有表皮棘皮增生和明显正角化过度角化的后代，与杂交品系无关。在这些杂交系中，只有 FVB；B6N(129S4)小鼠能存活到 250 天或更长时间，并产生了纯合 Card14 的重组近交系，这些系具有繁殖能力和鳞屑皮肤病。这表明，在小鼠中存在 PS 严重程度的修饰因子，就像人类家族性疾病一样。
