Molecular Genetics of Familial Mediterranean Fever

Abstract

Familial Mediterranean fever (FMF), an autoinflammatory disease, is very common in populations of Mediterranean ancestry. It is an autosomal recessive genetic disorder caused by mutations in the MEFV gene. The gene encodes a protein called pyrin or marenostrin which is involved in inflammatory pathways. From more than 150 mutations discovered in the MEFV gene so far, five (M694V, V726A, M680I, M694I and E148Q) are the most common in classically affected populations (Armenians, Arabs, Jews and Turks). Specific mutations and genotypes were found to be associated with severe or mild clinical forms of FMF, while various genetic and environmental modifying factors alter the phenotype. Some evolutionary aspects of the disease are being intensively studied: the origin of principal MEFV mutations, modification of pyrin's structure and function during phylogenesis, possible selective advantage of MEFV heterozygotes. Key concepts Familial Mediterranean fever (FMF, MIM 249100 ) is an autoinflammatory genetic disease with autosomal recessive mode of inheritance and is frequently encountered in populations of Mediterranean area. FMF is manifested by periodic attacks of fever and inflammation in the peritoneum, synovium or pleura. Renal amyloidosis is the most serious complication of the disease. The highest incidence of the disorder is registered in four ethnic groups (Armenians, Arabs, Jews and Turks) that are considered as ‘classically affected populations’. The illness is caused by mutations in the MEFV ( ME diterranean F e V er) gene, located on chromosome 16 (16p13.3) and is composed of 10 exons. MEFV encodes a protein named pyrin, or marenostrin, which is involved in innate immune response. More than 150 MEFV mutations have been discovered so far; five mutations (M694V, V726A, M680I and M694I in exon 10 and E148Q in exon 2) are the most frequent in classically affected populations. Clinical course of FMF depends on the MEFV genotype and is also under the influence of modifying factors of genetic and environmental nature. Main MEFV mutations were estimated to have a relatively ancient origin with subsequent spread during migrations and contacts between ancestral populations of the area. Unusually high incidence of MEFV mutations in classically affected populations might be explained by the hypothesis of heterozygote advantage (i.e. overdominance), when heterozygote genotype has higher relative fitness than either the homozygote dominant or homozygote recessive genotype.