Molecular etiology of familial Mediterranean fever

常染色体隐性遗传病家族性地中海热（FMF）患者， 与剧烈疼痛有关的不可预测的发热发作;疼痛最常见于关节 （关节炎）、腹部（腹膜炎）或胸部（胸膜炎）。偶尔，这种疾病会出现在皮肤上， 临床表现（丹毒样红斑）、心包炎、血管炎或肌痛。在许多患者中，淀粉样变性是一种 并发症，如果不治疗，可能危及生命。FMF是由pyrin基因的错义突变引起的， 在中性粒细胞、单核细胞、嗜酸性粒细胞、树突状细胞、滑膜细胞中表达的功能未知的蛋白 以及皮肤和腹膜成纤维细胞。这些细胞中的Pyrin表达由促炎细胞因子诱导 和LPS。因此，据推测，吡林调节炎症反应。进化 对pyrin分子的研究表明，在进化过程中，它一直处于积极的达尔文选择之下。 灵长类动物此外，在几个人类种族群体中，突变型pyrin等位基因的高频率支持了 突变等位基因的杂合子（选择性）优势。吡林的突变形式可能会增强身体的免疫力 清除重要病原体的能力。事实上，急性期反应物，先天免疫的重要因子， 不仅在患者中而且在突变等位基因携带者中都上调。Pyrin分子的结构分析 显示外显子1编码死亡结构域相关的结构基序（称为pyrin结构域或PyD）， 在一个不断增长的蛋白质家族中发现，该家族与炎症和先天免疫有关。鉴定 pyrin相互作用蛋白以及其他功能研究表明，pyrin直接连接到 细胞凋亡和细胞骨架信号级联，并且它调节细胞因子分泌。实验 本提案中描述的目的是进一步探索pyrin的这些功能，并确定 pyrin突变对细胞凋亡（Aim 1）、细胞骨架信号传导（Aim 2）和细胞因子产生（Aim 3）的影响。 最近鉴定的pyrin异构体也将在这些功能测定中进行检查，因为初步研究 表明不同的同种型可能发挥不同的功能。这些研究可以提供线索 了解FMF的分子发病机制，并可能揭示有关炎症的新信息， 一般的路径。事实上，与pyrin相互作用的蛋白质和含有pyrin结构域的家族成员， 已经与几种人类疾病有关，包括炎症性肠病，PAPA综合征， Muckle-Wells综合征、家族性寒冷性荨麻疹、Blau综合征和Behet病。

Patients with the autosomal recessive disease, Familial Mediterranean fever (FMF), suffer periodic, upredictable attacks of fever associated with severe pain; the pain is localized most commonly in joints (arthritis), abdomen (peritonitis) or chest (pleuritis). Occasionally, this disease presents with skin manifestations (erysipeloid erythema), pericarditis, vasculitis, or myalgia. In many patients, amyloidosis is a complication, and if untreated, this can be life-threatening. FMF is caused by missense mutations in pyrin, a protein of unknown function expressed in neutrophils, monocytes, eosinophils, dendritic cells, synovial cells and skin and peritoneal fibroblasts. Pyrin expression in these cells is induced by pro-inflammatory cytokines and by LPS. Thus, it has been speculated that pyrin modulates the inflammatory response. Evolutionary studies of the pyrin molecule indicate that it has been under positive Darwinian selection during evolution of the primates. Moreover, the high frequency of mutant pyrin alleles in several human ethnic groups supports a heterozygote (selective) advantage for the mutant allele. Mutant forms of pyrin may enhance the body's ability to clear important pathogen(s). Indeed, acute phase reactants, important agents of innate immunity, are up-regulated not only in patients but in carriers of mutant alleles. Structural analysis of the pyrin molecule revealed that exon 1 encodes a death-domain related structural motif (known as the pyrin domain or PyD) that is found in a growing family of proteins involved in inflammation and innate immunity. Identification of pyrin-interacting proteins as well as additional functional studies reveal that pyrin is linked directly to apoptotic and cytoskeletal signaling cascades, and that it modulates cytokine secretion. Experiments described in this proposal are designed to further explore these functions of pyrin and determine the effects of pyrin mutations on apoptosis (Aim 1); cytoskeletal signaling (Aim 2); and cytokine production (Aim 3). Recently identified pyrin isoforms will also be examined in these functional assays, since preliminary studies indicate that the various isoforms may function differently. Such studies could provide clues to understanding of the molecular pathogenesis of FMF, and may reveal new information about inflammatory pathways in general. In fact, pyrin-interacting proteins and pyrin domain-containing family members have already been connected to several human diseases, including inflammatory bowel disease, PAPA syndrome, Muckle-Wells sydrome, familial cold urticaria, Blau syndrome and Be_het's disease.