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Familial Mediterranean fever with a single MEFV mutation: where is the second hit?

ABSTRACT: OBJECTIVE:Familial Mediterranean fever (FMF) has traditionally been considered an autosomal-recessive disease; however, it has been observed that a substantial number of patients with clinical FMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high-penetrance FMF mutation. METHODS:MEFV and other candidate genes were sequenced by standard capillary electrophoresis. In 10 patients, the entire 15-kb MEFV genomic region was resequenced using hybridization-based chip technology. MEFV gene expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Pyrin protein levels were examined by Western blotting. RESULTS:A second MEFV mutation was not identified in any of the patients who were screened. Haplotype analysis did not identify a common haplotype that might be associated with the transmission of a second FMF allele. Western blots did not demonstrate a significant difference in pyrin levels between patients with a single mutation and those with a double mutation; however, FMF patients of both types showed higher protein expression as compared with controls and with non-FMF patients with active inflammation. Screening of genes encoding pyrin-interacting proteins identified rare mutations in a small number of patients, suggesting the possibility of digenic inheritance. CONCLUSION:Our data underscore the existence of a significant subset of FMF patients who are carriers of only 1 MEFV mutation and demonstrate that complete MEFV sequencing is not likely to yield a second mutation. Screening for the set of the most common mutations and detection of a single mutation appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine.

SUBMITTER: Booty MG

PROVIDER: S-EPMC2753538 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Familial Mediterranean fever with a single MEFV mutation: where is the second hit?

Booty Matthew G MG Chae Jae Jin JJ Masters Seth L SL Remmers Elaine F EF Barham Beverly B Le Julie M JM Barron Karyl S KS Holland Steve M SM Kastner Daniel L DL Aksentijevich Ivona I

Arthritis and rheumatism 20090601 6

<h4>Objective</h4>Familial Mediterranean fever (FMF) has traditionally been considered an autosomal-recessive disease; however, it has been observed that a substantial number of patients with clinical FMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high-penetrance FMF mutation.<h4>Methods</h4>MEFV and other candidate genes were sequenced by ...[more]

PMID: 19479870

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Project description:Familial Mediterranean fever (FMF) is a recessively inherited disorder predisposing to renal amyloidosis and associated with mutations in MEFV, a gene encoding a protein of unknown function. Differences in clinical expression have been attributed to MEFV-allelic heterogeneity, with the M694V/M694V genotype associated with a high prevalence of renal amyloidosis. However, the variable risk for patients with identical MEFV mutations to develop this severe complication, prevented by lifelong administration of colchicine, strongly suggests a role for other genetic and/or environmental factors. To overcome the well-known difficulties in the identification of modifying genetic factors, we investigated a relatively homogeneous population sample consisting of 137 Armenian patients with FMF from 127 independent families living in Armenia. We selected the SAA1, SAA2, and APOE genes-encoding serum amyloid proteins and apolipoprotein E, respectively-as well as the patients' sex, as candidate modifiers for renal amyloidosis. A stepwise logistic-regression analysis showed that the SAA1alpha/alpha genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other SAA1 genotypes (odds ratio [OR] 6. 9; 95% confidence interval [CI] 2.5-19.0). This association, which was present whatever the MEFV genotype, was extremely marked in patients homozygous for M694V (11/11). The risk for male patients of developing renal amyloidosis was fourfold higher than that for female patients (OR=4.0; 95% CI=1.5-10.8). This association, particularly marked in patients who were not homozygous for M694V (34.0% vs. 11.6%), was independent of SAA1-allelic variations. Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis. Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two MEFV-independent factors of genetic origin-SAA1 and sex-that act independently of each other.

Dataset Information

Familial Mediterranean fever with a single MEFV mutation: where is the second hit?

Publications

Familial Mediterranean fever with a single MEFV mutation: where is the second hit?

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