Fragouli E, Eliopoulos E, Petraki E, Sidiropoulos P, Aksentijevich I, Galanakis E, Kritikos H, Repa A, Fragiadakis G, Boumpas Dt, Goulielmos G N
Department of Internal Medicine, Medical School, University of Crete, Heraklion, Crete, Greece.
Clin Genet. 2008 Feb;73(2):152-9. doi: 10.1111/j.1399-0004.2007.00948.x. Epub 2007 Dec 29.
Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.
家族性地中海热（FMF）是一种常染色体隐性遗传病，其特征为发热反复发作且短暂，并伴有浆膜炎症，这是由编码吡啉蛋白的MEFV基因突变引起的。迄今为止，已鉴定出70多种与疾病相关的突变，几乎所有这些突变均代表错义核苷酸变化。FMF在地中海血统的患者中非常常见，尽管确切患病率尚不清楚，但希腊人被认为处于“中度风险”。在本研究中，我们对克里特岛本地人中的FMF患者进行了研究，该人群具有共同的遗传和文化背景。通过针对12种最常见的与FMF相关的突变进行分子分析，研究了71例患者以及158名健康对照中MEFV基因突变谱。我们发现，71例FMF患者中有59例（83.1%）至少有一个MEFV突变，5例患者为纯合子，54例为FMF相关突变的杂合子。12例患者（16.9%）未检测到突变。与高危人群一样，在克里特岛FMF患者中发现了常见的MEFV突变，其中M694V突变最为常见。M694V和M694I突变与严重表型相关，许多患者表现出不常见的临床表现，如丹毒样红斑或肾脏疾病。有趣的是，我们的20例（37%）杂合子FMF患者表现出严重表型。群体遗传学分析显示，健康克里特岛人群中FMF携带者频率约为6%（1:17），这使得克里特岛人与地中海盆地西部而非东部人群更为接近。最后，我们构建了一个三维模型，展示了吡啉的PRYSPRY结构域与半胱天冬酶-1的相互作用，并在该模型上绘制了根据疾病严重程度分类的MEFV突变。在这个模型中，半胱天冬酶-1的“柔性环”似乎无法接触到一些先前与轻度疾病相关的位置，这表明需要探索导致FMF的其他致病途径。
