Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder
Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder
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DOI：
10.1093/hmg/11.8.961
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发表时间：
2002-04-15
影响因子：
3.5
通讯作者：
Lovett, M
中科院分区：
文献类型：
--
作者：
Wise, CA;Gillum, JD;Lovett, M
Papa综合征(化脓性不孕性关节炎、坏疽脓皮病和痤疮，OMIM#604416)和家族性复发性关节炎是罕见的早期起病的遗传性疾病，主要影响皮肤和关节组织。反复发作的炎症会导致无菌的、化脓性的、富含中性粒细胞的物质在受累关节内积聚，最终导致严重的破坏。我们最近将Papa综合征和FRA的基因定位在染色体15q上，并提示它们是同一种疾病。我们现在已经通过鉴定CD2结合蛋白1(CD2BP1；GenBank登录号XM 044569)基因的共同分离致病突变在两个报告的这种疾病家系中证实了这一点。E250Q或A230T氨基酸替换发生在与酵母裂解沟相关蛋白CDC15高度同源的区域内。CD2BP1及其小鼠同源蛋白--脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白(PSTPIP1)是已知的与害虫蛋白酪氨酸磷酸酶(PTP)相互作用的接头蛋白。酵母双杂交试验表明，PTP Pest与E250Q和A230T突变蛋白的结合严重减少。以前的证据支持CD2BP1及其相互作用的蛋白在细胞骨架介导的事件中肌动蛋白重组中起着不可或缺的作用。我们假设，我们已经确定的致病突变损害了维持适当炎症反应所必需的生理信号。因此，我们建议将Papa综合征归类为自身炎症性疾病。这种CD2BP1介导的生化途径(S)可能在常见的炎症性疾病中发挥作用，这些疾病有明显的病因重叠，如类风湿性关节炎和炎症性肠病。
PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne, OMIM #604416) and familial recurrent arthritis (FRA) are rare inherited disorders of early onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. We recently localized the genes for PAPA syndrome and FRA to chromosome 15q and suggested that they are the same disorder. We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder. E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. CD2BP1 and its murine ortholog, proline-serine-threonine phosphatase interacting protein (PSTPIP1), are adaptor proteins known to interact with PEST-type protein tyrosine phosphatases (PTP). Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins. Previous evidence supports the integral role of CD2BP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. We hypothesize that the disease-causing mutations that we have identified compromise physiologic signaling necessary for the maintenance of proper inflammatory response. Accordingly we suggest classification of PAPA syndrome as an autoinflammatory disease. This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease.