The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation

Barbara R. Migeon, Shengyuan Luo, Mihir Jani, Peter Jeppesen

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88 Scopus citations


Mental retardation and a constellation of congenital malformations not usually associated with Turner syndrome are seen in some females with a mosaic 45,X/46,X,r(X) karyotype. Studies of these females show that the XIST locus on their tiny ring X chromosomes is either not present or not expressed. As XIST transcription is well correlated with inactivation of the X chromosome in female somatic cells and spermatogonia, nonexpression of the locus even when it is present suggests that these chromosomes are transcriptionally active. We examined the transcriptional activity of ring X chromosomes lacking XIST expression (XISTE), from three females with severe phenotypes. The two tiny ring X chromosomes studied with an antibody specific for the acetylated isoforms of histone H4 marking transcribed chromatin domains were labeled at a level consistent with their being active. We also examined two of the XISTE ring chromosomes to determine whether genes that are normally silent on an inactive X are expressed from these chromosomes. Analyses of hybrid cells show that TIMP, ZXDA, and ZXDB loci on the proximal short arm, and AR and PHKA1 loci on the long arm, are well expressed from the tiny ring X chromosome lacking XIST DNA. Studies of the ring chromosome that has XIST DNA but does not transcribe it show that its AR allele is transcribed along with the one on the normal X allele. These findings provide compelling evidence that (1) ring X chromosomes associated with severe phenotypes are unable to undergo X chromosome inactivation; (2) they represent chromosomal mutations affecting cis inactivation; and (3) the severe phenotype is due to functional disomy resulting from lack of dosage compensation for genes present within the ring chromosome.

Original languageEnglish (US)
Pages (from-to)497-504
Number of pages8
JournalAmerican journal of human genetics
Issue number3
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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