Skewed X-Chromosome Inactivation Is a Common Feature of X-Linked Mental Retardation Disorders

Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, ∼50 % demonstrate markedly skewed X inactivation (i.e., patterns 80:20), compared with only ∼10%of female control subjects (). Thus, skewedX inactivation is a relativelyP!.001 common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns 80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome. As a result of X-chromosome inactivation (Lyon 1961), heterozygous females are mosaic for X-linked gene ex-pression, with one population of cells expressing genes from the maternal X chromosome and the other pop-ulation expressing genes from the paternal X chromo-some (Nance 1964). The relative ratio of these two cell populations in a given female is frequently referred to as the “X-inactivation pattern. ” For female carriers of an X-linked mutation or structural abnormality, one cell population may be at a selective growth disadvantage, resulting in clonal outgrowth of cells with one or the other parental X chromosome active (Belmont 1996