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Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. Recently, it has been shown that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers, but the mechanisms underlying this skewing are unknown. ATR-X syndrome, caused by mutations in a ubiquitously expressed, chromatin-associated protein, provides a clear example of XLMR in which phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. Here, we have used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, we found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wild-type Atrx allele. Unexpectedly, selection does not appear to be the result of general cellular-viability defects in Atrx-deficient cells, since it is restricted to specific stages of development and is not ongoing throughout the life of the animal. Instead, there is evidence that selection results from independent tissue-specific effects. This illustrates an important mechanism by which skewed XCI may occur in carriers of XLMR and provides insight into the normal role of ATRX in regulating cell fate.

Original publication

DOI

10.1086/518369

Type

Journal article

Journal

Am J Hum Genet

Publication Date

06/2007

Volume

80

Pages

1138 - 1149

Keywords

Alleles, Animals, Crosses, Genetic, DNA Helicases, Disease Models, Animal, Female, Flow Cytometry, Fluorescent Antibody Technique, Indirect, Heterozygote, Humans, Immunohistochemistry, Male, Mental Retardation, X-Linked, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Mutation, Nuclear Proteins, Selection, Genetic, X Chromosome, X Chromosome Inactivation