X inactivation is a normal physiological process in which one X chromosome Opens in new window is largely inactivated in somatic cells in normal females (but not in normal males), thus equalizing the expression of most X-linked genes in the two sexes.
The clinical relevance of X inactivation is profound. It leads to females having two cell populations, one in which one of the X chromosomes is active, the other in which the other X chromosome is inactive.
Both cell populations in human females are readily detected for some disorders. For example, in Duchenne muscular dystrophy Opens in new window, female carriers Opens in new window exhibit typical mosaic expression Opens in new window, allowing carriers to be identified by dystrophin immunostaining.
Depending on the pattern of random X inactivation of the two X chromosomes, two female heterozygotes for an X-linked disease Opens in new window may have very different clinical presentations because they differ in the proportion of cells that have the mutant allele on the active X in a relevant tissue.
The most common method of analyzing X chromosome inactivation involves analysis of the methylation state of a restriction fragment length polymorphism in the androgen receptor gene itself, combined with assessment of CAG repeat length.
When this HpaII site is methylated, the restriction enzyme does not cut; when it is not methylated, the restriction enzyme can cut.
Methylation occurs on the inactivated X chromosome; in individuals heterozygous at the CAG repeat, it can be determined which allele is inactive.
Theoretically, X chromosome inaction should be random, with 50% of paternal alleles inactivated and 50% of maternal alleles inactivated within each subject. Skewed inactivation in cases but not controls, wherein one allele is preferentially methylated, would indicate a possible role for this epigenetic Opens in new window phenomenon in pathogenesis of the disease.
One small study detected skewed X chromosome inactivation in 5 of 34 women with hyperandrogenic hirsutism, wherein the shorter allele was often preferentially inactivated.
Similarly, a larger study documented preferential expression of longer CAG repeat alleles in PCOS; nonrandom X inactivation occurred more frequently in PCOS than in control women.
- Adapted from Thompson & Thompson Genetics in Medicine E-Book By Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard