Molecular etiology of familial Mediterranean fever

描述（由申请人提供）： 常染色体隐性遗传病家族性地中海热（FMF）患者会出现周期性、不可预测的发热发作，并伴有剧烈疼痛;疼痛最常见于关节（关节炎）、腹部（腹膜炎）或胸部（胸膜炎）。偶尔，这种疾病表现为皮肤表现（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的错义突变引起的，pyrin是一种在中性粒细胞、单核细胞、嗜酸性粒细胞、树突细胞、滑膜细胞以及皮肤和腹膜成纤维细胞中表达的功能未知的蛋白质。这些细胞中的Pyrin表达由促炎细胞因子和LPS诱导。因此，据推测，吡林调节炎症反应。对Pyrin分子的进化研究表明，在灵长类动物的进化过程中，它一直处于达尔文正选择的作用下。此外，在几个人类种族群体中的高频率的突变pyrin等位基因支持突变等位基因的杂合子（选择性）优势。吡林的突变形式可以增强身体清除重要病原体的能力。事实上，急性期反应物，先天免疫的重要代理商，上调不仅在患者，但在突变等位基因的载体。对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），该结构基序在参与炎症和先天免疫的蛋白质家族中发现。鉴定pyrin相互作用蛋白以及其他功能的研究表明，pyrin直接连接到细胞凋亡和细胞骨架信号级联，它调节细胞因子的分泌。本提案中描述的实验旨在进一步探索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。最近鉴定的吡林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，各种异构体可能具有不同的功能。这些研究可以为了解FMF的分子发病机制提供线索，并可能揭示有关一般炎症途径的新信息。事实上，pyrin相互作用蛋白和含有pyrin结构域的家族成员已经与几种人类疾病相关，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Bechet病。

DESCRIPTION (provided by applicant): Patients with the autosomal recessive disease, Familial Mediterranean fever (FMF), suffer periodic, unpredictable 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 syndrome, familial cold urticaria, Blau syndrome and Bechet's disease.