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. 1988 May;42(5):694–702.

A common fragile site at Xq27: theoretical and practical implications.

S A Ledbetter 1, D H Ledbetter 1
PMCID: PMC1715184  PMID: 3358421

Abstract

The fragile site at Xq27 (FRAXA) is associated with a common form of X-linked mental retardation (Martin-Bell syndrome). It is induced in culture by conditions of thymidylate stress and is generally considered a rare fragile site found only in association with an X-linked form of mental retardation. Using a somatic cell hybrid system, we previously demonstrated that fragile-X expression can be induced by thymidylate stress in normal X chromosomes at low levels (4%-5%). In the present report, significantly higher levels of fragile-X expression (6%-28%) have been induced in lymphocytes or lymphoblasts of all seven control males using high doses of aphidicolin (1.5 microM). Similar high levels of expression (10%-12%) were observed in both of two normal male chimpanzees (Pan troglodytes). These data demonstrate that Xq27 contains a common fragile site (FRAXD) that is ancestral to the divergence of man and the chimpanzee. Presence of a common and a rare fragile site in the same metaphase chromosome band does not prove that they are identical and may, in fact, represent two unrelated fragile sites. However, the possibility exists that the common fragile site at Xq27 may be the substrate for unequal recombination events that produces the rare fragile site associated with Martin-Bell syndrome. In addition, presence of a common fragile site at Xq27 may explain the occasional observation of low-frequency fragile-X expression in normal control individuals. Caution is therefore warranted in the interpretation of low-level fragile-X expression in diagnostic and prenatal diagnostic settings.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berger R., Bloomfield C. D., Sutherland G. R. Report of the Committee on Chromosome Rearrangements in Neoplasia and on Fragile Sites. Cytogenet Cell Genet. 1985;40(1-4):490–535. doi: 10.1159/000132181. [DOI] [PubMed] [Google Scholar]
  2. Chudley A. E., Hagerman R. J. Fragile X syndrome. J Pediatr. 1987 Jun;110(6):821–831. doi: 10.1016/s0022-3476(87)80392-x. [DOI] [PubMed] [Google Scholar]
  3. Daniel A. Clinical implications and classification of the constitutive fragile sites. Am J Med Genet. 1986 Jan-Feb;23(1-2):419–427. doi: 10.1002/ajmg.1320230134. [DOI] [PubMed] [Google Scholar]
  4. Glover T. W., Berger C., Coyle J., Echo B. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet. 1984;67(2):136–142. doi: 10.1007/BF00272988. [DOI] [PubMed] [Google Scholar]
  5. Glover T. W., Coyle-Morris J., Morgan R. Fragile sites: overview, occurrence in acute nonlymphocytic leukemia and effects of caffeine on expression. Cancer Genet Cytogenet. 1986 Jan 1;19(1-2):141–150. doi: 10.1016/0165-4608(86)90381-x. [DOI] [PubMed] [Google Scholar]
  6. Ikegami S., Taguchi T., Ohashi M., Oguro M., Nagano H., Mano Y. Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-alpha. Nature. 1978 Oct 5;275(5679):458–460. doi: 10.1038/275458a0. [DOI] [PubMed] [Google Scholar]
  7. Jenkins E. C., Brown W. T., Brooks J., Duncan C. J., Sanz M. M., Silverman W. P., Lele K. P., Masia A., Katz E., Lubin R. A. Low frequencies of apparently fragile X chromosomes in normal control cultures: a possible explanation. Exp Cell Biol. 1986;54(1):40–48. doi: 10.1159/000163342. [DOI] [PubMed] [Google Scholar]
  8. Jenkins E. C., Brown W. T., Wilson M. G., Lin M. S., Alfi O. S., Wassman E. R., Brooks J., Duncan C. J., Masia A., Krawczun M. S. The prenatal detection of the fragile X chromosome: review of recent experience. Am J Med Genet. 1986 Jan-Feb;23(1-2):297–311. doi: 10.1002/ajmg.1320230123. [DOI] [PubMed] [Google Scholar]
  9. Ledbetter D. H., Ledbetter S. A., Nussbaum R. L. Implications of fragile X expression in normal males for the nature of the mutation. Nature. 1986 Nov 13;324(6093):161–163. doi: 10.1038/324161a0. [DOI] [PubMed] [Google Scholar]
  10. Marlhens F., Achkar W. A., Aurias A., Couturier J., Dutrillaux A. M., Gerbault-Sereau M., Hoffschir F., Lamoliatte E., Lefrançois D., Lombard M. The rate of chromosome breakage is age dependent in lymphocytes of adult controls. Hum Genet. 1986 Aug;73(4):290–297. doi: 10.1007/BF00279088. [DOI] [PubMed] [Google Scholar]
  11. Nussbaum R. L., Airhart S. D., Ledbetter D. H. Recombination and amplification of pyrimidine-rich sequences may be responsible for initiation and progression of the Xq27 fragile site: an hypothesis. Am J Med Genet. 1986 Jan-Feb;23(1-2):715–721. doi: 10.1002/ajmg.1320230162. [DOI] [PubMed] [Google Scholar]
  12. Pembrey M. E., Winter R. M., Davies K. E. A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation. Am J Med Genet. 1985 Aug;21(4):709–717. doi: 10.1002/ajmg.1320210413. [DOI] [PubMed] [Google Scholar]
  13. Sherman S. L., Jacobs P. A., Morton N. E., Froster-Iskenius U., Howard-Peebles P. N., Nielsen K. B., Partington M. W., Sutherland G. R., Turner G., Watson M. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet. 1985;69(4):289–299. doi: 10.1007/BF00291644. [DOI] [PubMed] [Google Scholar]
  14. Sherman S. L., Morton N. E., Jacobs P. A., Turner G. The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet. 1984 Jan;48(Pt 1):21–37. doi: 10.1111/j.1469-1809.1984.tb00830.x. [DOI] [PubMed] [Google Scholar]
  15. Sutherland G. R., Baker E., Fratini A. Excess thymidine induces folate sensitive fragile sites. Am J Med Genet. 1985 Oct;22(2):433–443. doi: 10.1002/ajmg.1320220234. [DOI] [PubMed] [Google Scholar]
  16. Webb T. P., Rodeck C. H., Nicolaides K. H., Gosden C. M. Prenatal diagnosis of the fragile X syndrome using fetal blood and amniotic fluid. Prenat Diagn. 1987 Mar;7(3):203–214. doi: 10.1002/pd.1970070308. [DOI] [PubMed] [Google Scholar]
  17. Yunis J. J., Soreng A. L., Bowe A. E. Fragile sites are targets of diverse mutagens and carcinogens. Oncogene. 1987 Mar;1(1):59–69. [PubMed] [Google Scholar]
  18. Yunis J. J., Soreng A. L. Constitutive fragile sites and cancer. Science. 1984 Dec 7;226(4679):1199–1204. doi: 10.1126/science.6239375. [DOI] [PubMed] [Google Scholar]

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