PSORS2 Is Due to Mutations in CARD14
PSORS2 Is Due to Mutations in CARD14
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DOI：
10.1016/j.ajhg.2012.03.012
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发表时间：
2012-05-04
影响因子：
9.8
通讯作者：
Bowcock, Anne M.
中科院分区：
文献类型：
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作者：
Jordan, Catherine T.;Cao, Li;Bowcock, Anne M.
牛皮癣是一种常见的免疫介导的皮肤遗传疾病，约30%的病例与关节炎有关。此前，我们在一个有多个牛皮癣和牛皮癣关节炎病例的欧洲家族中进行了全基因组连锁扫描后，将PSORS2(牛皮癣易感基因2)定位于染色体区域17q25.3-QTER。在一个有多名银屑病患者成员的台湾家庭中也观察到了与PSORS2的关联。在caspase招募结构域家族成员14(CARD14)中，我们通过基因组捕获和DNA测序鉴定了与银屑病分离的独特的功能获得突变。突变c.349G>；A(p.Gly117Ser)(欧洲血统)和c.349+5G>；A(台湾家系)改变了CARD14外显子3和4之间的剪接。在一名散发性、早发性、泛发性脓疱型银屑病的儿童中发现了一种新的CARD14突变c.413A>；C(p.Glu138Ala)。与野生型CARD14相比，pGly117Ser和pGlu138Ala替换导致角质形成细胞中核因子kB的激活增强和银屑病相关基因亚群的上调。这些基因包括趋化因子(C-C基序)、配体20(CCL20)和白介素8(IL8)。CARD14主要定位于正常皮肤表皮的基底层和基底层，而在银屑病皮损中，CARD14在基底层表达减少，在基底层表达更广泛。我们认为，在一个可能包括表皮损伤的触发事件之后，CARD14罕见的功能获得突变启动了一个过程，包括角质形成细胞招募炎性细胞。这延续了表皮炎症和再生的恶性循环，这一循环是牛皮癣的标志。
Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.