Letter | Published:

A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation

Nature Genetics volume 17, pages 353356 (1997) | Download Citation

Subjects

Abstract

X-chromosome inactivation is the process by which a cell recognizes the presence of two copies of an X chromosome early in the development of XX embryos and chooses one to be active and one to be inactive1. Although it is commonly believed that the initiation of X inactivation is random, with an equal probability (50:50) that either X chromosome will be the inactive X in a given cell, significant variation in the proportion of cells with either X inactive is observed both in mice heterozygous for alleles at the Xce locus2 and among normal human females in the population3–5. Families in which multiple females demonstrate extremely skewed inactivation patterns that are otherwise quite rare in the general population are thought to reflect possible genetic influences on the X-inactivation process5–7. Here we report a rare cytosine to guanine mutation in the XIST minimal promoter that underlies both epigenetic and functional differences between the two X chromosomes in nine females from two unrelated families. All females demonstrate preferential inactivation of the X chromosome carrying the mutation, suggesting that there is an association between alterations in the regulation of XIST expression and X-chromosome inactivation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Gene action in the X-chromosome of the mouse (Mus musculus L). Nature 190, 372–373 (1961).

  2. 2.

    , & Controlling elements in the mouse X-chromosome: I. Interaction with the X-linked genes. Genet. Res. 14, 223–235 (1969).

  3. 3.

    Genetic tests with a sex-linked marker: glucose-6-phosphate dehydrogenase. Cold Spring Harbor Symp. Quant. Biol. 29, 415–424 (1964).

  4. 4.

    , , & Tissue specificity of X-chromosome inactivation patterns. Blood 83, 2899–2905 (1994).

  5. 5.

    Sex chromosomes and X chromosome inactivation. in The Metabolic and Molecular Basis of Inherited Disease, 7th ed. (eds Scriver, C.R. et al.) 719–737 (McGraw-Hill, New York, 1995).

  6. 6.

    et al. Heritability of X chromosome-inactivation phenotype in a large family. Am. J. Hum. Genet. 58, 1111–1119 (1996).

  7. 7.

    , & Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency). Proc. Natl. Acad. Sci. USA 88, 39–42 (1991).

  8. 8.

    et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991).

  9. 9.

    et al. Characterisation of a murine gene expressed from the inactive X chromosome. Nature 351, 325–329 (1991).

  10. 10.

    et al. Conservation of position and exclusive expression of mouse Xistfrom the inactive X chromosome. Nature 351, 329–331 (1991).

  11. 11.

    et al. Expression of X/st during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72, 171–182 (1993).

  12. 12.

    , , , & , Xist gene is required in cis for X chromosome inactivation. Nature 379, 131–137 (1996).

  13. 13.

    Pinpointing the centre. Nature 379, 116–117 (1996).

  14. 14.

    , , , & Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 11, 156–166 (1997).

  15. 15.

    , , & X/st has properties of the X-chromosome inactivation centre. Nature 386, 272–275 (1997).

  16. 16.

    , , , & Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51, 1229–1239 (1992).

  17. 17.

    Genetic control of X inactivation and processes leading to X-inactivation skewing. Am. J. Hum. Genet. 58, 1101–1108 (1996).

  18. 18.

    , & Quantitative RT-PCR assays show X/st RNA levels are low in mouse female adult tissue, embryos and embryoid bodies. Development 120, 3529–3536 (1994).

  19. 19.

    & Role play in X-inactivation. Hum. Mol. Genet. 3, 1481–1485 (1994).

  20. 20.

    , & Direct detection of non-random X chromosome inactivation by use of a transcribed polymorphism in the XIST gene. Eur. J. Hum. Genet. 3, 333–343 (1995).

  21. 21.

    et al. Frequent deletions of the human X-chromosome distal short arm result from recombination between low copy repetitive elements. Cell 61, 603–610 (1990).

  22. 22.

    & Deletions and translocations involving the distal short arm of the human X chromosome: review and hypotheses. Hum. Mol. Genet. 1, 221–226 (1992).

  23. 23.

    & An assay for X inactivation based on differential methylation at the fragile X locus, FMR1. Am. J. Med. Genet. 64, 27–30 (1996).

  24. 24.

    , & Evolutionary conservation of possible functional domains of the human and murine XIST genes. Hum. Mol. Genet. 2, 663–672 (1993).

  25. 25.

    , & Identification and characterization of the human XIST gene promoter: implications for models of X chromosome inactivation. Nucleic Acids Res. 25, 2661–2671 (1997).

  26. 26.

    et al. X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12. Am. J. Med. Genet 64, 50–58 (1996).

  27. 27.

    , , & Inheritance of skewed X chromosome inactivation in a large family with an X-linked recessive deafness syndrome. Am. J. Med. Genet 64, 31–34 (1996).

  28. 28.

    , , & Selection in blood cells from female carriers of the fragile X syndrome: inverse correlation between age and proportion of active X chromosomes carrying the full mutation. J. Med. Genet 28, 830–836 (1991).

  29. 29.

    , , , & X-linked a-thalessemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21. 31 by X inactivation and linkage analysis. Am. J. Hum. Genet. 51, 1136–1149 (1992).

  30. 30.

    X chromosome inactivation, XIST, and pursuit of the X inactivation center. Cell 86, 5–7 (1996).

  31. 31.

    & Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279 (1997).

  32. 32.

    , , & A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell 86, 83–94 (1996).

  33. 33.

    et al. An expression based clonality assay at the human androgen receptor locus (HUMARA) on chromosome X. Nucleic Acids Res. 22, 697–698 (1994).

Download references

Author information

Affiliations

  1. Department of Genetics, Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

    • Robert M. Plenge
    • , Brian D. Hendrich
    •  & Huntington F. Willard
  2. J.C. Self Research Institute, The Greenwood Center, Greenwood, South Carolina, USA.

    • Charles Schwartz
  3. Department of Pediatrics, Division of Genetics, University of Miami School of Medicine, Miami, Florida, USA.

    • J. Fernando Arena
  4. Fels Institute for Cancer Research and Molecular Biology, Philadelphia, Pennsylvania, USA.

    • Anna Naumova
    •  & Carmen Sapienza
  5. Mothercare Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, London WC1N1EH, UK.

    • Robin M. Winter

Authors

  1. Search for Robert M. Plenge in:

  2. Search for Brian D. Hendrich in:

  3. Search for Charles Schwartz in:

  4. Search for J. Fernando Arena in:

  5. Search for Anna Naumova in:

  6. Search for Carmen Sapienza in:

  7. Search for Robin M. Winter in:

  8. Search for Huntington F. Willard in:

Corresponding author

Correspondence to Huntington F. Willard.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng1197-353