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. 1987 Nov;117(3):587–599. doi: 10.1093/genetics/117.3.587

Proposed Mechanism of Inheritance and Expression of the Human Fragile-X Syndrome of Mental Retardation

Charles D Laird 1
PMCID: PMC1203233  PMID: 3692144

Abstract

A mechanism is proposed for the inheritance and expression of the fragile-X-linked syndrome of mental retardation in humans. Two independent events are required for expression of the syndrome: the fragile- X mutation, and X chromosome inactivation in pre-oogonial cells. The fragile-X mutation at site Xq27 has little or no effect until the chromosome is inactivated in a female as part of the process of dosage compensation. At a stage where the inactivated X chromosome would normally be reactivated in preparation for oogenesis, the mutation results in a local block to the reactivation process. This block to reactivation leads to mental retardation in progeny by reducing the level of products from the unreactivated Xq27 region in male cells, and, for a heterozygous female, in somatic cells in which the normal X chromosome has been inactivated. Published data relevant to this proposed mechanism are discussed.

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Selected References

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  1. Brown W. T., Jenkins E. C., Krawczun M. S., Wisniewski K., Rudelli R., Cohen I. L., Fisch G., Wolf-Schein E., Miezejeski C., Dobkin C. The fragile X syndrome. Ann N Y Acad Sci. 1986;477:129–150. doi: 10.1111/j.1749-6632.1986.tb40329.x. [DOI] [PubMed] [Google Scholar]
  2. Camerino G., Mattei M. G., Mattei J. F., Jaye M., Mandel J. L. Close linkage of fragile X-mental retardation syndrome to haemophilia B and transmission through a normal male. Nature. 1983 Dec 15;306(5944):701–704. doi: 10.1038/306701a0. [DOI] [PubMed] [Google Scholar]
  3. Cattanach B. M. Position effect variegation in the mouse. Genet Res. 1974 Jun;23(3):291–306. doi: 10.1017/s0016672300014932. [DOI] [PubMed] [Google Scholar]
  4. Chandra H. S., Brown S. W. Chromosome imprinting and the mammalian X chromosome. Nature. 1975 Jan 17;253(5488):165–168. doi: 10.1038/253165a0. [DOI] [PubMed] [Google Scholar]
  5. Crouse H V. The Controlling Element in Sex Chromosome Behavior in Sciara. Genetics. 1960 Oct;45(10):1429–1443. doi: 10.1093/genetics/45.10.1429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fialkow P. J. Primordial cell pool size and lineage relationships of five human cell types. Ann Hum Genet. 1973 Jul;37(1):39–48. doi: 10.1111/j.1469-1809.1973.tb01813.x. [DOI] [PubMed] [Google Scholar]
  7. Froster-Iskenius U., McGillivray B. C., Dill F. J., Hall J. G., Herbst D. S. Normal male carriers in the fra(X) form of X-linked mental retardation (Martin-Bell syndrome). Am J Med Genet. 1986 Jan-Feb;23(1-2):619–631. doi: 10.1002/ajmg.1320230156. [DOI] [PubMed] [Google Scholar]
  8. Gartler S. M., Liskay R. M., Campbell B. K., Sparkes R., Gant N. Evidence for two functional X chromosomes in human oocytes. Cell Differ. 1972 Oct;1(4):215–218. doi: 10.1016/0045-6039(72)90039-5. [DOI] [PubMed] [Google Scholar]
  9. Holliday R., Pugh J. E. DNA modification mechanisms and gene activity during development. Science. 1975 Jan 24;187(4173):226–232. [PubMed] [Google Scholar]
  10. Howell R. T., McDermott A. Replication status of the fragile X chromosome, fra(X)(q27), in three heterozygous females. Hum Genet. 1982;62(3):282–284. doi: 10.1007/BF00333538. [DOI] [PubMed] [Google Scholar]
  11. LYON M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961 Apr 22;190:372–373. doi: 10.1038/190372a0. [DOI] [PubMed] [Google Scholar]
  12. Lubs H. A. A marker X chromosome. Am J Hum Genet. 1969 May;21(3):231–244. [PMC free article] [PubMed] [Google Scholar]
  13. Lyon M. F. X-chromosome inactivation and developmental patterns in mammals. Biol Rev Camb Philos Soc. 1972 Jan;47(1):1–35. doi: 10.1111/j.1469-185x.1972.tb00969.x. [DOI] [PubMed] [Google Scholar]
  14. Mareni C., Migeon B. R. Fragile X syndrome: search for phenotypic manifestations at loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase. Am J Hum Genet. 1981 Sep;33(5):752–761. [PMC free article] [PubMed] [Google Scholar]
  15. Migeon B. R., Shapiro L. J., Norum R. A., Mohandas T., Axelman J., Dabora R. L. Differential expression of steroid sulphatase locus on active and inactive human X chromosome. Nature. 1982 Oct 28;299(5886):838–840. doi: 10.1038/299838a0. [DOI] [PubMed] [Google Scholar]
  16. Nesbit M. N. X chromosome inactivation mosaicism in the mouse. Dev Biol. 1971 Oct;26(2):252–263. doi: 10.1016/0012-1606(71)90125-4. [DOI] [PubMed] [Google Scholar]
  17. Oberlé I., Heilig R., Moisan J. P., Kloepfer C., Mattéi G. M., Mattéi J. F., Boué J., Froster-Iskenius U., Jacobs P. A., Lathrop G. M. Genetic analysis of the fragile-X mental retardation syndrome with two flanking polymorphic DNA markers. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1016–1020. doi: 10.1073/pnas.83.4.1016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Opitz J. M. On the gates of hell and a most unusual gene. Am J Med Genet. 1986 Jan-Feb;23(1-2):1–10. doi: 10.1002/ajmg.1320230102. [DOI] [PubMed] [Google Scholar]
  19. Riggs A. D. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet. 1975;14(1):9–25. doi: 10.1159/000130315. [DOI] [PubMed] [Google Scholar]
  20. Sager R., Kitchin R. Selective silencing of eukaryotic DNA. Science. 1975 Aug 8;189(4201):426–433. [PubMed] [Google Scholar]
  21. Shapiro L. J., Mohandas T., Weiss R., Romeo G. Non-inactivation of an x-chromosome locus in man. Science. 1979 Jun 15;204(4398):1224–1226. doi: 10.1126/science.156396. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Steinbach P. Mental impairment in Martin-Bell syndrome is probably determined by interaction of several genes: simple explanation of phenotypic differences between unaffected and affected males with the same X chromosome. Hum Genet. 1986 Mar;72(3):248–252. doi: 10.1007/BF00291888. [DOI] [PubMed] [Google Scholar]
  24. Therman E., Sarto G. E., Patau K. Center for Barr body condensation on the proximal part of the human Xq: a hypothesis. Chromosoma. 1974 Jan 29;44(4):361–366. doi: 10.1007/BF00284895. [DOI] [PubMed] [Google Scholar]
  25. Tuckerman E., Webb T., Bundey S. E. Frequency and replication status of the fragile X, fra(X)(q27-28), in a pair of monozygotic twins of markedly differing intelligence. J Med Genet. 1985 Apr;22(2):85–91. doi: 10.1136/jmg.22.2.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Uchida I. A., Freeman V. C., Jamro H., Partington M. W., Soltan H. C. Additional evidence for fragile X activity in heterozygous carriers. Am J Hum Genet. 1983 Sep;35(5):861–868. [PMC free article] [PubMed] [Google Scholar]
  27. Uchida I. A., Joyce E. M. Activity of the fragile X in heterozygous carriers. Am J Hum Genet. 1982 Mar;34(2):286–293. [PMC free article] [PubMed] [Google Scholar]

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