Abstract
BackgroundFamilial Mediterranean Fever (FMF) is an autoinflammatory disorder caused by mutations in the MEFV gene. These mutations appear in different populations with different frequencies and their caused symptom severities vary from mild to moderate to severe depending on the mutation type.MethodsIn this study, we analyzed the mutations that have been reported in the MEFV gene from symptomatic FMF patients and compared their frequencies in different populations from the 1000 Genome and the Exome databases, using statistical clustering. We also analyzed the nucleotide and amino acid substitution patterns across the MEFV gene.ResultsWe found 16 (8%) nonsynonymous mutations outside exon 10 that did not cluster with known disease‐causing mutations (DCMs), due to their high frequencies in other populations. We also studied the substitution patterns for nucleotides and amino acids to determine the conserved and variable regions in the MEFV gene. In general more nonsynonymous substitutions were reported in exons 2, 3, and 10 from the FMF database (symptomatic FMF patients) compared to the 1000 Genome and the Exome databases. The same was true for amino acid (AA) substitutions where there were 1.5 times more radical (RAD) to conservative (CON) changes. However, when it came to AA substitutions exon 10 was quite conserved with a RAD/CON ratio of 0.9. In fact, we report that the most severe FMF symptoms are caused by conservative mutations in two highly conserved exon 10 regions.ConclusionWe found presumptive FMF‐causing mutations that did not cluster with DCMs based on their allele frequencies. We also observed that the type of mutation is less likely to determine the severity of the FMF symptoms; rather it was the location of the mutations that was the determining factor.
Highlights
Familial Mediterranean Fever (FMF, OMIM 249100) is an autoinflammatory disorder characterized by recurrent episodes of fever, peritonitis, pleuritis, synovitis, and complications of amyloidosis (Sohar et al 1967; French FMF Consortium. 1997)
We found 16 (8%) nonsynonymous mutations outside exon 10 that did not cluster with known disease-causing mutations (DCMs), due to their high frequencies in other populations
We studied the substitution patterns for nucleotides and amino acids to determine the conserved and variable regions in the MEFV gene
Summary
Familial Mediterranean Fever (FMF, OMIM 249100) is an autoinflammatory disorder characterized by recurrent episodes of fever, peritonitis, pleuritis, synovitis, and complications of amyloidosis (Sohar et al 1967; French FMF Consortium. 1997). FMF is considered the prototype among the hereditary recurrent fevers as the most frequent and the first whose gene has been identified (Heller et al 1955) This autosomal recessive condition is usually caused by mutations in the MEFV gene (OMIM 608107; GenBank NM_000243.2), which has 10 exons and codes for a protein called pyrin (French FMF Consortium 1997; International FMF Consortium 1997). Weinert’s group identified a group of 28 disease-causing mutations (DCMs) and their impact on the protein structure of pyrin (Weinert et al 2009) These mutations were designated as reference mutations for clustering analysis in this study and referred to as DCMs. Fever (FMF) is an autoinflammatory disorder caused by mutations in the MEFV gene. These mutations appear in different populations with different frequencies and their caused symptom severities vary from mild to moderate to severe depending on the mutation type
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