Touitou I, Picot M C, Domingo C, Notarnicola C, Cattan D, Demaille J, Koné-Paut I
Laboratory of Genetics, Arnaud de Villeneuve Hospital, Montpellier, France.
Arthritis Rheum. 2001 Jan;44(1):163-9. doi: 10.1002/1529-0131(200101)44:1<163::AID-ANR20>3.0.CO;2-Z.
Familial Mediterranean fever (FMF) is a genetically recessive inflammatory disease caused by mutations in the MEFV gene. Most patients of non-Ashkenazi Jewish ancestry or those who are homozygous for M694V manifest a severe disease course, but some express a mild form of the disease. We therefore searched for other genes which could possibly be implicated in the disease phenotype. We tested MICA (major histocompatibility complex class I chain-related gene A) because it has been associated with a number of other inflammatory disorders.
One hundred fifty FMF probands and their family members were evaluated. The MEFV gene was screened by a combination of denaturing gradient-gel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system. The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products were loaded onto sequencing gels and subjected to autoradiography.
The contribution of MICA to the FMF phenotype was confirmed after adjustment for the patient's ancestry and for the MEFV genotype. MEFV was individually the most important prognostic factor for the disease. However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was aggravated if patients also inherited MICA-A9 (OR 6.3). In contrast, the frequency of attacks was found to be dramatically reduced (OR 0.16) in patients with MICA-A4.
We have identified the first FMF modifier locus, MICA. FMF is the first model of a Mendelian disease associated with MICA. These results clarify, at least partly, the inconsistent phenotype-MEFV correlation in FMF.
家族性地中海热（FMF）是一种由MEFV基因突变引起的常染色体隐性遗传性炎症性疾病。大多数非阿什肯纳兹犹太血统的患者或M694V纯合子患者表现为严重的病程，但也有一些患者表现为疾病的轻度形式。因此，我们寻找了其他可能与疾病表型相关的基因。我们检测了MICA（主要组织相容性复合体I类链相关基因A），因为它与许多其他炎症性疾病有关。
对150例FMF先证者及其家庭成员进行评估。采用变性梯度凝胶电泳、限制性片段长度多态性和扩增阻滞突变系统相结合的方法对MEFV基因进行筛查。将生物素标记的聚合酶链反应产物加载到测序凝胶上并进行放射自显影后，分析外显子5中的MICA跨膜多态性。
在对患者的血统和MEFV基因型进行校正后，证实了MICA对FMF表型的影响。MEFV单独是该疾病最重要的预后因素。然而，如果患者还遗传了MICA-A9，M694V纯合性对疾病发病年龄的影响（OR 2.3）会加重（OR 6.3）。相比之下，发现MICA-A4患者的发作频率显著降低（OR 0.16）。
我们鉴定出第一个FMF修饰位点MICA。FMF是与MICA相关的孟德尔疾病的首个模型。这些结果至少部分阐明了FMF中表型与MEFV相关性不一致的问题。
