LACK OF X INACTIVATION ASSOCIATED WITH MATERNAL X ISODISOMY - EVIDENCE FOR A COUNTING MECHANISM PRIOR TO X INACTIVATION DURING HUMAN EMBRYOGENESIS

We have previously reported functional disomy for X-linked genes in fe males with tiny ring X chromosomes and a phenotype significantly more abnormal than Turner syndrome. In such cases the disomy results from f ailure of these X chromosomes to inactivate because they lack DNA sequ ences essential for cis X inactivation. Here we describe a novel molec ular mechanism for functional X disomy that is associated with materna l 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 mater nal 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 chromo some 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 mad e; and (3) support the hypothesis that the X chromosome counting mecha nism involves chromosomal imprinting, occurs prior to the onset of ran dom inactivation, and is required for subsequent inactivation of the c hromosome.