pediatrics
Overview of Sex Chromosome Abnormalities
Lyon hypothesis (X inactivation)
By virtue of having 2 X chromosomes, females have 2 loci for every X-linked gene, as compared with a single locus in males. This imbalance would seem to cause a genetic “dosage” problem. However, according to the Lyon hypothesis, 1 of the 2 X chromosomes in each female somatic cell is inactivated genetically early in embryonic life (on or about day 16). In fact, no matter how many X chromosomes are present, all but 1 are inactivated. However, molecular genetic studies have shown that some genes on the inactivated X chromosome (or chromosomes) remain functional, and these few are essential to normal female development.XISTis the gene responsible for inactivating the genes of the X chromosome, producing RNA that triggers inactivation. Whether the maternal or paternal X is inactivated usually is a random event within each cell at the time of inactivation; that same X then remains inactive in all descendant cells. Thus, all females are essentially mosaic, with some cells having an active maternal X and others having an active paternal X. Because of random X-inactivation, all females are mosaics, with some cells having an active maternal X and others having an active paternal X. Sometimes, random statistical distribution of inactivation in the relatively small number of cells present at the time of inactivation results in a particular descendant tissue having a preponderance of active maternal or paternal X chromosomes (skewed inactivation). Skewed inactivation may account for the occasional manifestation of minor symptoms in females who are heterozygous for X-linked disorders such as hemophilia and muscular dystrophy (all would presumably be asymptomatic if they had a 50:50 distribution of active X chromosomes). Skewed inactivation also may occur by postinactivation selection. 