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Am J Hum Genet. Aug 1994; 55(2): 356–364.
PMCID: PMC1918357

Linkage Disequilibrium and Haplotype Studies of Chromosome 8p 11.1-21.1 Markers and Werner Syndrome


Werner syndrome (WS) is an autosomal recessive disorder, characterized as a progeroid syndrome, previously mapped to the 8p 11.1-21.1 region. Because WS is so rare, and because many patients are from consanguineous marriages, fine localization of the gene by traditional meiotic mapping methods is unlikely to succeed. Here we present the results of a search for a region that exhibits linkage disequilibrium with the disorder, under the assumption that identification of such a region may provide an alternative method of narrowing down the location of WRN, the gene responsible for WS. We present allele frequencies in Japanese and Caucasian cases and controls for D8S137, D8S131, D8S87, D8S278, D8S259, D8S283, fibroblast growth factor receptor 1, ankyrin 1, D8S339, and two polymorphisms in glutathione reductase (GSR), covering ~16.5 cM in total. We show that three of the markers examined—D8S339 and both polymorphisms in the GSR locus—show strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, we show that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as eight or nine independent WRN mutations in these two populations.

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  • Aksentijevich I, Pras E, Gruberg L, Shen Y, Holman K, Helling S, Prosen L, Sutherland GR, Richards RI, Dean M, et al. Familial Mediterranean fever (FMF) in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis. Am J Hum Genet. 1993 Sep;53(3):644–651. [PMC free article] [PubMed]
  • Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327–337. [PubMed]
  • CEPPELLINI R, SINISCALCO M, SMITH CA. The estimation of gene frequencies in a random-mating population. Ann Hum Genet. 1955 Oct;20(2):97–115. [PubMed]
  • Chakraborty R, Lidsky AS, Daiger SP, Güttler F, Sullivan S, Dilella AG, Woo SL. Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria. Hum Genet. 1987 May;76(1):40–46. [PubMed]
  • Epstein CJ, Martin GM, Schultz AL, Motulsky AG. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 1966 May;45(3):177–221. [PubMed]
  • Fujita R, Hanauer A, Sirugo G, Heilig R, Mandel JL. Additional polymorphisms at marker loci D9S5 and D9S15 generate extended haplotypes in linkage disequilibrium with Friedreich ataxia. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1796–1800. [PMC free article] [PubMed]
  • Goto M, Rubenstein M, Weber J, Woods K, Drayna D. Genetic linkage of Werner's syndrome to five markers on chromosome 8. Nature. 1992 Feb 20;355(6362):735–738. [PubMed]
  • Goto M, Takeuchi F, Tanimoto K, Miyamoto T. Clinical, demographic, and genetic aspects of the Werner syndrome in Japan. Adv Exp Med Biol. 1985;190:245–261. [PubMed]
  • Harley HG, Brook JD, Floyd J, Rundle SA, Crow S, Walsh KV, Thibault MC, Harper PS, Shaw DJ. Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet. 1991 Jul;49(1):68–75. [PMC free article] [PubMed]
  • Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. [PubMed]
  • Lander ES, Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987 Jun 19;236(4808):1567–1570. [PubMed]
  • Levinson G, Gutman GA. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol. 1987 May;4(3):203–221. [PubMed]
  • MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R, et al. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. [PubMed]
  • Martin GM. Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects Orig Artic Ser. 1978;14(1):5–39. [PubMed]
  • Martin GM, Sprague CA, Epstein CJ. Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype. Lab Invest. 1970 Jul;23(1):86–92. [PubMed]
  • Mitchison HM, Thompson AD, Mulley JC, Kozman HM, Richards RI, Callen DF, Stallings RL, Doggett NA, Attwood J, McKay TR, et al. Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci. Genomics. 1993 May;16(2):455–460. [PubMed]
  • Petrukhin K, Fischer SG, Pirastu M, Tanzi RE, Chernov I, Devoto M, Brzustowicz LM, Cayanis E, Vitale E, Russo JJ, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet. 1993 Dec;5(4):338–343. [PubMed]
  • Schellenberg GD, Martin GM, Wijsman EM, Nakura J, Miki T, Ogihara T. Homozygosity mapping and Werner's syndrome. Lancet. 1992 Apr 18;339(8799):1002–1002. [PubMed]
  • Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 Dec;5(4):344–350. [PubMed]
  • Thomas W, Drayna D. A polymorphic dinucleotide repeat at the D8S339 locus. Hum Mol Genet. 1993 Jun;2(6):828–828. [PubMed]
  • Thomas W, Rubenstein M, Goto M, Drayna D. A genetic analysis of the Werner syndrome region on human chromosome 8p. Genomics. 1993 Jun;16(3):685–690. [PubMed]
  • Tomfohrde J, Wood S, Schertzer M, Wagner MJ, Wells DE, Parrish J, Sadler LA, Blanton SH, Daiger SP, Wang Z, et al. Human chromosome 8 linkage map based on short tandem repeat polymorphisms: effect of genotyping errors. Genomics. 1992 Sep;14(1):144–152. [PubMed]
  • Weber JL, May PE. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed]
  • Weber JL, Wong C. Mutation of human short tandem repeats. Hum Mol Genet. 1993 Aug;2(8):1123–1128. [PubMed]
  • Weissenbach J, Gyapay G, Dib C, Vignal A, Morissette J, Millasseau P, Vaysseix G, Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. [PubMed]
  • Yu CE, Anderson L, Oshima J, Schellenberg GD. Dinucleotide repeat polymorphism at the D8S131 locus. Hum Mol Genet. 1994 Jan;3(1):211–211. [PubMed]

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