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Mitotic stability of fragile X mutations in differentiated cells indicates early post–conceptional trinucleotide repeat expansion

Nature Genetics volume 4, pages 140142 (1993) | Download Citation

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Abstract

We demonstrate hre that somatic variation of CGG repeat length is based on a mosaic of cells with different but stable FMR–1 alleles and does not reflect permanent mitotic instability. The length of a particular allele in an individual cell was maintained in progeny cells establishing a clone. The mutation patterns of multiple repeats in the DNA of fetal tissues were identical and did not significantly change during proliferation in vitro. It is proposed that genotype mosaicism and expansion to full mutation are generated post–conceptionally by the same molecular mechanism in a particular window of early development.

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References

  1. 1.

    et al. Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature 349, 624–626 (1991).

  2. 2.

    et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).

  3. 3.

    et al. Fragile X genotype characterized by an unstable region of DNA. Science 252, 1179–1181 (1991).

  4. 4.

    et al. Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866 (1991).

  5. 5.

    et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

  6. 6.

    et al. Mapping of DNA instability at the fragile X to a trinucletide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).

  7. 7.

    et al. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).

  8. 8.

    et al. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. New Engl. J. Med. 325, 1673–1681 (1991).

  9. 9.

    et al. Genotype mosaicism in fragile X fetal tissues. Hum. Genet. 89, 114–116 (1992).

  10. 10.

    et al. Analysts of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am. J. med. Genet. 43, 208–216 (1992).

  11. 11.

    & Fragile X syndrome: the molecular picture comes into focus. Trends Genet. 8, 249–254 (1992).

  12. 12.

    , & in Genome analysis, a practical approach (ed Davies, K. E.) 41–72 (IRL, 1988).

  13. 13.

    , & Increased sister chromatid exchange frequency at Xq27 site in affected fragile X males. Am. J. med. Genet. 26, 909 (1987).

  14. 14.

    Induction of the fragile X on BrdU-substituted chromosomes with direct visualization of sister chromatid exchanges on banded chromosomes. Hum. Genet. 81, 377–381 (1989).

  15. 15.

    Fragile X chromosome in fibroblasts: Longitudinal study on technical variation. Clin. Genet. 23, 229 (1983).

  16. 16.

    et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

  17. 17.

    et al. Efficient and reliable direct diagnosis of the fragile X mental retardation syndrome. New Engl. J. Med. 325, 1673–1681 (1991).

  18. 18.

    et al. Heritable unstable DNA sequences and hypermethylation associated with fragile X syndrome in Japanese families. Clin. Genet. 43, 34–38 (1993).

  19. 19.

    et al. Segregation of the fragile X mutation from an affected male to his normal daughter. Hum. molec. Genet. 7, 511–515 (1992).

  20. 20.

    & Fragile X expression and X inactivation. II. The fragile site at Xq27.3 has a basic function in the pathogenesis of fragile X-linked mental retardation. Hum. Genet. 87, 421–24 (1991).

  21. 21.

    , , , & Inheritance of the fragile X syndrome: Size of fragile X premutation is a major determinant of the transition to full mutation. J. med. Genet. 29, 794–801 (1992).

  22. 22.

    & An embryonic model to explain cytogenetic inconsistencies observed in chorionic villus versus fetal tissue. Prenat. Diagn. 8, 119–129 (1988).

  23. 23.

    , & Regional and temporal changes in the pattern of X chromosome replication during early postimplantation development of the female mouse. Chromosoma 85, 275–286 (1982).

  24. 24.

    et al. Molecular heterogeneity of the fragile X syndrome. Nucl. Acids Res. 19, 4355–4359 (1991).

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  1. Abteilung Klinische Genetik, Universität Ulm, Parkstraße 11, D-7900 Ulm, Germany

    • Doris Wöhrle
    • , Ingeborg Hennig
    • , Walther Vogel
    •  & Peter Steinbach

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DOI

https://doi.org/10.1038/ng0693-140

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