MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications.

Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessary surgery. Renal amyloidosis, prevented by colchicine, is the most severe complication of FMF, a disorder associated with mutations in the MEFV gene. To evaluate the diagnostic and prognostic value of MEFV-gene analysis, we investigated 90 Armenian FMF patients from 77 unrelated families that were not selected through genetic-linkage analysis. Eight mutations, one of which (R408Q) is new, were found to account for 93% of the 163 independent FMF alleles, with both FMF alleles identified in 89% of the patients. In several instances, family studies provided molecular evidence for pseudodominant transmission and incomplete penetrance of the disease phenotype. The M694V homozygous genotype was found to be associated with a higher prevalence of renal amyloidosis and arthritis, compared with other genotypes (P=.0002 and P=.006, respectively). The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families.

[1]  H. Ostrer,et al.  Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. , 1999, American journal of human genetics.

[2]  D. Kastner,et al.  Diagnosis of Familial Mediterranean Fever by a Molecular Genetics Method , 1998, Annals of Internal Medicine.

[3]  J. Weissenbach,et al.  Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). , 1998, Human molecular genetics.

[4]  D. Kastner,et al.  Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. , 1998, Medicine.

[5]  D. Zemer,et al.  Criteria for the diagnosis of familial Mediterranean fever. , 1997, Arthritis and rheumatism.

[6]  Jacques Demaille,et al.  A candidate gene for familial Mediterranean fever , 1997, Nature Genetics.

[7]  F. Collins,et al.  Ancient Missense Mutations in a New Member of the RoRet Gene Family Are Likely to Cause Familial Mediterranean Fever , 1997, Cell.

[8]  A. Bakkaloğlu,et al.  Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis , 1997, European Journal of Pediatrics.

[9]  R. Cotton,et al.  Slowly but surely towards better scanning for mutations. , 1997, Trends in genetics : TIG.

[10]  L. Kruglyak,et al.  Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246. , 1996, American journal of human genetics.

[11]  Y. Yuval,et al.  Dominant inheritance in two families with familial Mediterranean fever (FMF). , 1995, American journal of medical genetics.

[12]  N. Mechti,et al.  Molecular Cloning of a New Interferon-induced Factor That Represses Human Immunodeficiency Virus Type 1 Long Terminal Repeat Expression (*) , 1995, The Journal of Biological Chemistry.

[13]  P. Freemont,et al.  A novel zinc finger coiled-coil domain in a family of nuclear proteins. , 1992, Trends in biochemical sciences.

[14]  D. Kastner,et al.  Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. , 1992, The New England journal of medicine.

[15]  J. Rotter,et al.  Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency. , 1989, American journal of medical genetics.

[16]  G. Freeman,et al.  rpt-1, an intracellular protein from helper/inducer T cells that regulates gene expression of interleukin 2 receptor and human immunodeficiency virus type 1. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Zemer,et al.  Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. , 1986, The New England journal of medicine.

[18]  D. Alling,et al.  Colchicine therapy for familial mediterranean fever. A double-blind trial. , 1974, The New England journal of medicine.

[19]  B. Modan,et al.  A controlled trial of colchicine in preventing attacks of familial mediterranean fever. , 1974, The New England journal of medicine.

[20]  E. Sohar,et al.  FAMILIAL MEDITERRANEAN FEVER , 1959, Definitions.

[21]  E. Sohar,et al.  Amyloidosis as the sole manifestation of familial Mediterranean fever (FMF). Further evidence of its genetic nature. , 1962, Annals of internal medicine.

[22]  A. Bernot,et al.  Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF) , 1998, European Journal of Human Genetics.

[23]  George J. Feldman,et al.  Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22 , 1997, Nature Genetics.