Familial Mediterranean Fever With a Single MEFV Mutation Where Is the Second Hit?
Familial Mediterranean Fever With a Single MEFV Mutation Where Is the Second Hit?
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DOI：
10.1002/art.24569
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发表时间：
2009-06-01
影响因子：
--
通讯作者：
Aksentijevich, Ivona
中科院分区：
文献类型：
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作者：
Booty, Matthew G.;Chae, Jae Jin;Aksentijevich, Ivona
目标。家族性地中海热（IMF）传统上被认为是常染色体隐性疾病；然而，据观察，大量临床IMF患者仅具有1种可证实的MEFV突变。本研究的目的是在46例临床诊断为FMF且仅携带1个高外显率IMF突变的患者中进行广泛搜索，寻找第二个MEFV突变。用标准毛细管电泳法对MEFV等候选基因进行测序。在10例患者中，使用基于杂交的芯片技术对整个15kb的MEFV基因组区域进行了重新测序。通过定量逆转录-聚合酶链反应检测MEFV基因表达水平。Western blotting检测Pyrin蛋白水平。在所有接受筛查的患者中未发现第二种MEFV突变。单倍型分析未发现可能与第二个IMF等位基因传播相关的共同单倍型。Western blots未显示单突变患者和双突变患者pyrin水平有显著差异；然而，两种类型的FMF患者与对照组和活动性炎症的非FMF患者相比，蛋白表达均较高。筛选编码pyrin相互作用蛋白的基因在少数患者中发现了罕见的突变，提示基因遗传的可能性。我们的数据强调存在一个重要的IMF患者亚群，他们只携带1个MEFV突变，并证明完整的MEFV测序不太可能产生第二个突变。在出现临床症状的情况下，筛选一组最常见的突变和检测单一突变似乎足以诊断IMF和开始秋水仙碱试验。
Objective. Familial Mediterranean fever (IMF) has traditionally been considered an autosomal-recessive disease; however, it has been observed that a substantial number of patients with clinical IMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high-penetrance IMF mutation.Methods. MEFV and other candidate genes were sequenced by standard capillary electrophoresis. In 10 patients, the entire 15-kb MEFV genomic region was resequenced using hybridization-based chip technology. MEFV gene expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Pyrin protein levels were examined by Western blotting.Results. A second MEFV mutation was not identified in any of the patients who were screened. Haplotype analysis did not identify a common haplotype that might be associated with the transmission of a second IMF allele. Western blots did not demonstrate a significant difference in pyrin levels between patients with a single mutation and those with a double mutation; however, FMF patients of both types showed higher protein expression as compared with controls and with non-FMF patients with active inflammation. Screening of genes encoding pyrin-interacting proteins identified rare mutations in a small number of patients, suggesting the possibility of digenic inheritance.Conclusion. Our data underscore the existence of a significant subset of IMF patients who are carriers of only 1 MEFV mutation and demonstrate that complete MEFV sequencing is not likely to yield a second mutation. Screening for the set of the most common mutations and detection of a single mutation appears to be sufficient in the presence of clinical symptoms for the diagnosis of IMF and the initiation of a trial of colchicine.