Related Experiment Video
Updated: Jul 25, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
The MICA region determines the first modifier locus in familial Mediterranean fever
I Touitou1, M C Picot, C Domingo
1Laboratory of Genetics, Arnaud de Villeneuve Hospital, Montpellier, France.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
The major histocompatibility complex class I chain-related gene A (MICA) acts as a modifier locus for Familial Mediterranean fever (FMF). MICA influences disease severity and attack frequency, clarifying inconsistent MEFV gene correlations.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder.
- Mutations in the MEFV gene are the primary cause of FMF.
- Inconsistent disease severity observed in FMF patients suggests the involvement of additional genetic factors.
Purpose of the Study:
- To investigate the role of the major histocompatibility complex class I chain-related gene A (MICA) as a potential modifier gene in FMF.
- To identify genetic factors contributing to the variable clinical presentation of FMF.
Main Methods:
- Genetic analysis of 150 FMF probands and family members.
- Screening of the MEFV gene using denaturing gradient-gel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system.
- Analysis of MICA transmembrane polymorphism in exon 5 using polymerase chain reaction and sequencing gels.
Main Results:
- MICA was identified as a significant modifier locus influencing FMF phenotype, independent of patient ancestry and MEFV genotype.
- M694V homozygosity in the MEFV gene exacerbated early disease onset when combined with MICA-A9.
- The MICA-A4 allele was associated with a significant reduction in FMF attack frequency.
Conclusions:
- MICA is the first identified modifier locus for FMF, establishing FMF as a model Mendelian disease associated with MICA.
- These findings help explain the variable correlation between MEFV genotype and FMF phenotype.
- MICA genotyping may aid in predicting FMF disease course and severity.
More Related Videos
Related Concept Videos
01:11Genetic Lingo
01:43Sex-linked Disorders
02:23Master Transcription Regulators