title: Lack of X inactivation associated with maternal X isodisomy: evidence for a counting mechanism prior to X inactivation during human embryogenesis.
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.
authors.affiliation: Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3914, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Migeon
authors.forename: P
authors.initials: P
authors.lastname: Jeppesen
authors.forename: B S
authors.initials: BS
authors.lastname: Torchia
authors.forename: S
authors.initials: S
authors.lastname: Fu
authors.forename: M A
authors.initials: MA
authors.lastname: Dunn
authors.forename: J
authors.initials: J
authors.lastname: Axelman
authors.forename: B J
authors.initials: BJ
authors.lastname: Schmeckpeper
authors.forename: J
authors.initials: J
authors.lastname: Fantes
authors.forename: R T
authors.initials: RT
authors.lastname: Zori
authors.forename: D J
authors.initials: DJ
authors.lastname: Driscoll
mesh_terms: D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D004261:DNA Replication; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D006822:Hybrid Cells; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D009030:Mosaicism; D011003:Ploidies; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012729:Sex Chromosome Aberrations; D014158:Transcription, Genetic; D014424:Turner Syndrome / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome
chemical_list: D005819:Genetic Markers