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  • The sex chromosome constitution differs between males and females. The Y chromosome is normally found only in males and is responsible for primary sex determination, but has relatively few other functions. The X chromosome is present in normal males in one copy and in normal females in two copies. X chromosome inactivation acts as a means of dosage compensation by inactivating one of the two X chromosomes in female somatic cells early in development.

  • The active and inactive X chromosomes are distinguished by a number of features. In addition to being largely transcriptionally repressed, the inactive X becomes late replicating, heterochromatic (forming the Barr body in interphase nuclei), and extensively methylated at gene control regions. All these features can be used in clinical cytogenetic settings to determine whether an X chromosome is active or inactive. X chromosome inactivation is believed to be random at the blastocyst stage of development. Accordingly, females heterozygous for X-linked traits are mosaic for two cell types that express one or the other X chromosome. Considerable variation occurs in the proportion of the two expected cell types in different individuals. At least 5 to 10 percent of normal females demonstrate extreme skewing of X inactivation, in which a cell type expressing one X predominates over the other cell type. In heterozygotes for an X-linked disorder, this skewing of X inactivation correlates with the degree to which females demonstrate symptoms of the X-linked disease. X inactivation is, therefore, a key determinant of the clinical phenotype in female carriers of X-linked diseases. In several disorders, such as X-linked immunodeficiencies, postinactivation cell selection is typically observed in affected tissues, and nonrandom X inactivation of the X carrying the mutant allele is observed.

  • Not all X-linked genes are subject to X chromosome inactivation. Of the few hundred X-linked genes examined for X inactivation status, several dozen genes have been described that “escape” X inactivation and continue to be expressed from both active and otherwise inactive X chromosomes. These genes are located in several regions of the X chromosome and can be clustered together or interspersed with genes known to be subject to X inactivation. Extrapolating from current studies, it is possible that many hundreds of the expected total of several thousand X-linked genes will escape X inactivation. These genes are candidates to explain the clinical symptoms found in patients with X chromosome aneuploidy in whom additional X chromosomes are invariably inactive.

  • X inactivation requires a locus—the X inactivation center—on the long arm of the chromosome in band Xq13.2. In most instances, structurally abnormal X chromosomes found in patients contain the X inactivation center and are nonrandomly inactivated. The gene for inactive X [Xi]-specific transcripts (XIST) gene maps within the X inactivation center region and plays a critical role in X inactivation. XIST is only expressed from inactive X chromosomes and produces an RNA molecule that remains associated with the inactive X. Although its mechanism(s) of action is not understood completely, XIST...

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