Molecular Genetics of Familial Mediterranean Fever

Abstract

Abstract Familial Mediterranean fever (FMF) is an autoinflammatory disease, which is prevalent in populations of the Mediterranean ancestry. Traditionally, FMF was considered as an autosomal recessive genetic disorder; however, several studies showed that a heterozygote state might also result in disease. Mutations responsible for the disease are located in the MEFV gene encoding a protein called pyrin/marenostrin/TRIM20. FMF is characterised by seemingly unprovoked periodic activation of innate immunity, with fever and serosal inflammation. Among more than 300 mutations in the MEFV gene, five mutations (M694V, V726A, M680I, M694I and E148Q) are the most common in classically affected populations (Armenians, Arabs, Jews and Turks). Disease severity depends on specific MEFV mutations and also on a number of other genetic or environmental modifiers. Certain evolutionary aspects of the disease were intensively investigated including the origin of major MEFV mutations, structure‐and‐function and evolution of pyrin and potential selective advantage of heterozygous carriage. Key Concepts Familial Mediterranean fever (FMF, MIM 249100) is an autoinflammatory genetic disease, and it is prevalent in populations of Mediterranean origin. The highest incidence of the disorder is documented in four ethnic groups Armenians, Arabs, Jews and Turks, which are considered as ‘classically affected populations’. Clinical manifestations of FMF include periodic occurrence of fever and inflammation in the peritoneum, synovium or pleura. Renal amyloidosis is the most serious complication of the disease. The disease is caused by mutations in the MEFV ( ME diterranean F e V er) gene, which is composed of 10 exons and located on chromosome 16 (16p13.3). MEFV encodes a protein named pyrin or marenostrin or TRIM20, which is a key component of innate immunity. Presently, more than 300 MEFV mutations have been identified. Five mutations (M694V, V726A, M680I and M694I in exon 10 and E148Q in exon 2) are most frequent in classically affected populations. Severity of FMF depends on specific MEFV mutations as well as on a number of other genetic and environmental modifiers. The most common MEFV mutations display a relatively ancient origin, with the subsequent penetration to other populations following migratory and interbreeding processes. The high carriage rate of MEFV mutations in classically affected populations may be explained by a potential selection for the heterozygote genotype, which may have conferred some sort of selective advantage for populations in the area but currently there is no proof for this.