Molecular etiology of familial Mediterranean fever

患有常染色体隐性遗传病的家族性地中海热(FMF)患者， 与剧烈疼痛相关的不可预知的发烧发作；疼痛最常发生在关节 (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、脉管炎或肌痛。在许多患者中，淀粉样变性是一种 并发症，如果不治疗，这可能会危及生命。FMF是由吡喃的错义突变引起的， 中性粒细胞、单核细胞、嗜酸性粒细胞、树突状细胞、滑膜细胞表达功能不明的蛋白质 皮肤和腹膜成纤维细胞。促炎症细胞因子诱导这些细胞表达吡喃 和脂多糖。因此，人们推测，吡喃对炎症反应有调节作用。进化论 对吡喃分子的研究表明，在进化过程中，它一直处于达尔文的积极选择之下。 灵长类动物。此外，在几个人类种族群体中，突变的比林等位基因的高频率支持一种 突变等位基因的杂合子(选择性)优势。突变形式的吡喃可能会增强人体的 清除重要病原体的能力(S)。事实上，急性期的反应物，先天免疫的重要媒介， 不仅在患者中上调，而且在突变等位基因携带者中也上调。吡喃分子的结构分析 揭示了外显子1编码一个与死亡域相关的结构基序(称为吡林域或PYD)，它 在越来越多的参与炎症和先天免疫的蛋白质家族中被发现。身份识别 与吡喃相互作用的蛋白质以及更多的功能研究表明，吡喃直接与 细胞凋亡和细胞骨架信号级联，并调节细胞因子的分泌。实验 旨在进一步探讨吡喃的这些功能，并确定 吡喃突变对细胞凋亡的影响(目标1)；细胞骨架信号(目标2)；以及细胞因子的产生(目标3)。 最近确定的吡咯异构体也将在这些功能分析中进行检查，因为初步研究 表明不同的异构体可能起不同的作用。这样的研究可以提供线索 了解FMF的分子发病机制，并可能揭示炎症的新信息 一般的路径。事实上，吡喃相互作用蛋白和含有吡喃结构域的家族成员都有 已经与几种人类疾病有关，包括炎症性肠病，爸爸综合症， Muckle-Wells综合征、家族性寒冷性荨麻疹、Blu综合征和白氏病。

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.