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Refined mapping of the gene causing familial Mediterranean fever, by linkage and homozygosity studies
I Aksentijevich1, E Pras, L Gruberg
1Artchritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by attacks of fever and serosal inflammation; the biochemical basis is unknown. We recently reported linkage of the gene causing FMF (designated "MEF") to two markers on chromosome 16p. To map MEF more precisely, we have now tested nine 16p markers. Two-point and multipoint linkage analysis, as well as a study of recombinant haplotypes, placed MEF between D16S94 and D16S80, a genetic interval of about 9 cM. We also examined rates of homozygosity for markers in this region, among offspring of consanguineous marriages. For eight of nine markers, the rate of homozygosity among 26 affected inbred individuals was higher than that among their 20 unaffected sibs. Localizing MEF more precisely on the basis of homozygosity rates alone would be difficult, for two reasons: First, the high FMF carrier frequency increases the chance that inbred offspring could have the disease without being homozygous by descent at MEF. Second, several of the markers in this region are relatively nonpolymorphic, with a high rate of homozygosity, regardless of their chromosomal location.
Insights
Familial Mediterranean fever (FMF) gene (MEF) is located on chromosome 16p. Precise mapping of MEF was achieved using linkage analysis and homozygosity studies in affected individuals.
Area of Science:
- Genetics
- Human Molecular Genetics
Background:
- Familial Mediterranean fever (FMF) is an autosomal recessive inflammatory disorder with unknown biochemical causes.
- Previous studies linked the FMF gene (MEF) to chromosome 16p.
Purpose of the Study:
- To precisely map the MEF gene within the chromosome 16p region.
- To refine the genetic localization of the FMF gene.
Main Methods:
- Utilized two-point and multipoint linkage analysis with nine 16p markers.
- Studied recombinant haplotypes to define the MEF locus.
- Assessed marker homozygosity rates in offspring from consanguineous marriages.
Main Results:
- The MEF gene was localized to a 9 cM genetic interval between markers D16S94 and D16S80.
- Eight of nine tested markers showed higher homozygosity rates in affected inbred individuals compared to unaffected siblings.
Conclusions:
- Precise localization of the MEF gene on chromosome 16p was established.
- Homozygosity studies provided supplementary evidence but were complicated by high FMF carrier frequency and marker polymorphism levels.