Lack of X inactivation associated with maternal X isodisomy: Evidence for a counting mechanism prior to X inactivation during human embryogenesis

Barbara R. Migeon, Peter Jeppesen, Beth S. Torchia, Sidong Fu, Melanie A. Dunn, Joyce Axelman, Barbara J. Schmeckpeper, Judy Fantes, Robert T. Zori, Daniel J. Driscoll

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Abstract

We have previously reported functional disomy for X-linked genes in females with tiny ring X chromosomes and a phenotype significantly more abnormal than Turner syndrome. In such cases the disomy results from failure of these X chromosomes to inactivate because they lack DNA sequences essential for cis X inactivation. Here we describe a novel molecular mechanism for functional X disomy that is associated with maternal isodisomy. In this case, the severe mental retardation and multiple congenital abnormalities in a female with a mosaic 45,X/ 46,X,del(X) (q21.3-qter)/ 46X,r(X) karyotype are associated with overexpression of the genes within Xpter to Xq21.31 in many of her cells. Her normal X, ring X, and deleted linear X chromosomes originate from the same maternal X chromosome, and all are transcriptionally active. None expresses X inactive specific transcript (XIST), although the locus and region of the putative X inactivation center (XIC) are present on both normal and linear deleted X chromosomes. To our knowledge, this is the first report of a functional maternal X isodisomy, and the largest X chromosome to escape inactivation. In addition, these results (1) show that cis inactivation does not invariably occur in human females with two X chromosomes, even when the XIC region is present on both of them; (2) provide evidence for a critical time prior to the visible onset of X inactivation in the embryo when decisions about X inactivation are made; and (3) support the hypothesis that the X chromosome counting mechanism involves chromosomal imprinting, occurs prior to the onset of random inactivation, and is required for subsequent inactivation of the chromosome.

Original languageEnglish (US)
Pages (from-to)161-170
Number of pages10
JournalAmerican journal of human genetics
Volume58
Issue number1
StatePublished - Jan 1 1996

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Migeon, B. R., Jeppesen, P., Torchia, B. S., Fu, S., Dunn, M. A., Axelman, J., Schmeckpeper, B. J., Fantes, J., Zori, R. T., & Driscoll, D. J. (1996). Lack of X inactivation associated with maternal X isodisomy: Evidence for a counting mechanism prior to X inactivation during human embryogenesis. American journal of human genetics, 58(1), 161-170.