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)的患者会出现周期性的、不可预测的发烧发作，并伴随着剧烈的疼痛；疼痛最常见的是关节(关节炎)、腹部(腹膜炎)或胸部(胸膜炎)。有时，这种疾病表现为皮肤症状(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，可能会危及生命。FMF是一种功能未知的蛋白质，表达在中性粒细胞、单核细胞、嗜酸性粒细胞、树突状细胞、滑膜细胞以及皮肤和腹膜成纤维细胞中，是一种错义突变引起的。促炎症细胞因子和脂多糖诱导这些细胞表达吡喃。因此，人们推测，吡喃对炎症反应有调节作用。对比林分子的进化研究表明，在灵长类动物的进化过程中，它一直处于达尔文的积极选择之下。此外，突变的吡喃等位基因在几个种族群体中的频率很高，这支持了突变等位基因的杂合子(选择性)优势。突变形式的比林可能会增强人体清除重要病原体的能力(S)。事实上，急性期反应物是先天免疫的重要因素，不仅在患者身上上调，在突变等位基因携带者中也是如此。对比林分子的结构分析表明，外显子1编码一个与死亡结构域相关的结构基序(称为比林结构域或PYD)，该结构基序存在于参与炎症和先天免疫的蛋白质家族中。对吡喃相互作用蛋白的鉴定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有关，并调节细胞因子的分泌。这项建议中描述的实验旨在进一步探索比林的这些功能，并确定比林突变对细胞凋亡(目标1)、细胞骨架信号(目标2)和细胞因子产生(目标3)的影响。最近确定的吡咯异构体也将在这些功能分析中被检测，因为初步研究表明不同的异构体可能有不同的功能。这些研究可以为了解FMF的分子发病机制提供线索，并可能揭示一般炎症途径的新信息。事实上，吡喃结合蛋白及其结构域家族成员已被发现与多种人类疾病有关，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Bechet‘s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.