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J Med Genet. 1997 July; 34(7): 573–578.
PMCID: PMC1050998

Genetic linkage study of familial Mediterranean fever (FMF) to 16p13.3 and evidence for genetic heterogeneity in the Turkish population.


Familial Mediterranean fever (FMF) is an autosomal recessive condition that is almost entirely restricted to the non-Askhenazi Jews, Arabs, Armenians, and Turks. Genetic linkage study of a large group of non-Turkish families has previously mapped the FMF locus to the 16p13.3 region and shown that this locus resides 0.305 cM distal to D16S246. Furthermore, allelic association has also been shown with D16S3070 (75%) and D16S3275 (66%). However, no genetic heterogeneity has been described for any of the three major reported groups of FMF families. Here, we describe the genetic linkage relationship of the fourth major group of Turkish families and report the first evidence for genetic heterogeneity of this condition. Two point linkage analysis and haplotype inspection of 15 DNA markers from the reported region of the FMF locus identified tight linkage in a group of six Turkish FMF families. A maximum lod score of 9.115 at theta = 0.00 was observed for D16S3024. Nine other DNA markers provided similar evidence of linkage with lod score values of above 5.21. However, two other FMF families were completely unlinked to this region of chromosome 16. Haplotype construction of DNA markers in five consanguineous linked families showed that a segment of homozygosity has been conserved for D16S3070 and D16S2617. No other DNA markers showed any such conservation. Therefore, we suggested that these two markers reside in close proximity to the FMF locus. Furthermore, we observed 80% allelic association with D16S2617 but no association with D16S3070 or any other DNA markers from the FMF critical region. In summary, we conclude that our Turkish families are also linked to the reported FMF locus at 16p13.3, there is a genetic heterogeneity for this condition at least in our group of Turkish families, and D16S2617 is in linkage disequilibrium in the Turkish FMF families. Combination of this study with previously published observations suggests that the FMF locus resides between D16S246 and D16S3070/D16S2617 and within a region of about 250-300 kb.

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  • Rogers DB, Shohat M, Petersen GM, Bickal J, Congleton J, Schwabe AD, Rotter JI. Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency. Am J Med Genet. 1989 Oct;34(2):168–172. [PubMed]
  • Saatci U, Ozen S, Bakkaloglu A, Besbas N. Familial Mediterranean fever: a misnomer? Lancet. 1994 Feb 19;343(8895):485–485. [PubMed]
  • Ozer FL, Kaplaman E, Zileli S. Familial Mediterranean fever in Turkey. A report of twenty cases. Am J Med. 1971 Mar;50(3):336–339. [PubMed]
  • Ozdemir AI, Sokmen C. Familial Mediterranean fever among the Turkish people. Am J Gastroenterol. 1969 Apr;51(4):311–316. [PubMed]
  • Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. 1967 Aug;43(2):227–253. [PubMed]
  • Zemer D, Livneh A, Danon YL, Pras M, Sohar E. Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum. 1991 Aug;34(8):973–977. [PubMed]
  • Saatci U, Bakkaloglu A, Ozen S, Besbas N. Familial Mediterranean fever and amyloidosis in children. Acta Paediatr. 1993 Aug;82(8):705–706. [PubMed]
  • Pras E, Aksentijevich I, Gruberg L, Balow JE, Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med. 1992 Jun 4;326(23):1509–1513. [PubMed]
  • Shohat M, Bu X, Shohat T, Fischel-Ghodsian N, Magal N, Nakamura Y, Schwabe AD, Schlezinger M, Danon Y, Rotter JI. The gene for familial Mediterranean fever in both Armenians and non-Ashkenazi Jews is linked to the alpha-globin complex on 16p: evidence for locus homogeneity. Am J Hum Genet. 1992 Dec;51(6):1349–1354. [PubMed]
  • Localization of the familial Mediterranean fever gene (FMF) to a 250-kb interval in non-Ashkenazi Jewish founder haplotypes. The French FMF Consortium. Am J Hum Genet. 1996 Sep;59(3):603–612. [PubMed]
  • Saatci U, Ozdemir S, Ozen S, Bakkaloglu A. Serum concentration and urinary excretion of beta 2-microglobulin and microalbuminuria in familial Mediterranean fever. Arch Dis Child. 1994 Jan;70(1):27–29. [PMC free article] [PubMed]
  • Fasman KH, Cuticchia AJ, Kingsbury DT. The GDB Human Genome Data Base anno 1994. Nucleic Acids Res. 1994 Sep;22(17):3462–3469. [PMC free article] [PubMed]
  • Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. [PubMed]
  • Dib C, Fauré S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. [PubMed]
  • Sheffield VC, Weber JL, Buetow KH, Murray JC, Even DA, Wiles K, Gastier JM, Pulido JC, Yandava C, Sunden SL, et al. A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps. Hum Mol Genet. 1995 Oct;4(10):1837–1844. [PubMed]
  • Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PubMed]
  • Schäffer AA, Gupta SK, Shriram K, Cottingham RW., Jr Avoiding recomputation in linkage analysis. Hum Hered. 1994 Jul-Aug;44(4):225–237. [PubMed]
  • Aksentijevich I, Gruberg L, Pras E, Balow JE, Jr, Kovo M, Gazit E, Dean M, Pras M, Kastner DL. Evidence for linkage of the gene causing familial Mediterranean fever to chromosome 17q in non-Ashkenazi Jewish families: second locus or type I error? Hum Genet. 1993 Jul;91(6):527–534. [PubMed]
  • Aksentijevich I, Pras E, Gruberg L, Shen Y, Holman K, Helling S, Prosen L, Sutherland GR, Richards RI, Ramsburg M, et al. Refined mapping of the gene causing familial Mediterranean fever, by linkage and homozygosity studies. Am J Hum Genet. 1993 Aug;53(2):451–461. [PubMed]
  • Drenth JP, Mariman EC, Van der Velde-Visser SD, Ropers HH, Van der Meer JW. Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for familial Mediterranean fever. International Hyper-IgD Study Group. Hum Genet. 1994 Dec;94(6):616–620. [PubMed]
  • Schwabe AD, Peters RS. Familial Mediterranean Fever in Armenians. Analysis of 100 cases. Medicine (Baltimore) 1974 Nov;53(6):453–462. [PubMed]

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