Research Notes: X-chromosome Inactivation Skewness in PWS due to UPD

Females have two X chromosomes - one from each parent. At the point when the female embryo consists of about 8 to 16 cells, each cell randomly inactivates one of the X chromosomes and so each of the daughter cells of a particular lineage cell will inherit that choice of X chromosome. The inactivation process normally results in about a 50-50 split between paternally and maternally expressed X chromosomes in the cells (that is, balanced mosaicism), but in females with X-chromosome inactivation (XCI) skewness, more of either the maternal or paternal X chromosomes were inactivated. Generally, the cutoff for determining the presence of "X-inactivation skewness" is when 75-80% of the X chromosomes in a person's cells are from one parent. "Extreme skewness" is when 90-95% of the X chromosomes in a person's cells are from one parent.

X-inactivation skewness in females is important for two main reasons. One is the issue of X-linked recessive disorders such as hemophilia, etc. X-linked disorders are normally considered male disorders because they have only one X chromosome, so a single recessive gene on that X chromosome will cause the disorders. A female with a balanced expression of paternal and maternal X chromosomes typically will not manifest a X-linked disorder even if the X chromosomes from one of her parents carries a defect because the other half of her X-chromosomes don't have the defect and so the genes on that chromosome are expressed normally. She will be a carrier for that disorder, though, and her offspring could possibly have the disorder if the father also has that defect on his X-chromosome. However, there are very rare occasions when a female does manifest a X-linked disorder. There are two mechanisms by which that can occur. One is because the female inherits a X-chromosome with the defect from her mother and the father has the disorder, so all of her X chromosomes carry the defect. The other mechanism occurs when one of a female's X-chromosomes contains a defect and her X chromosomes are skewed toward the one carrying the defect. In such cases, the severity of the disorder is typically related to how skewed her X chromosomes are. The other reason that XCI skewness in females might be important has to do with the inheritance of genes that carry an increased susceptibility to developing certain diseases. Recent studies suggest, for example, that XCI skewness may be a risk factor for the development of both sporadic and familial breast cancer.

So what does XCI skewness have to do with Prader-Willi syndrome (PWS)? According to the following study, extreme XCI skewness (>90%) was found in 24% of females with PWS due to uniparental disomy (UPD), but in only 4% of controls. The 24% of females with PWS due to UPD who also have extreme XCI skewness are therefore at theoretical risk for also having an X-linked recessive disorder.

X-chromosome skewness occurs for various reasons. One is pure chance - keep tossing a coin 15 times and you'll eventually wind up with a series with 75-95% heads, for example. There is also an "inactivation center" on X chromosomes that operates similar to the "imprinting center" that is part of the affected PWS region on chromosome 15, that is, it is apparently used to mark the chromosome as active or inactive, thereby preventing the expression of most but not all genes on inactive X chromosomes. Defects in the inactivation center (de novo or inherited) can allow normally inactivated genes to escape X inactivation (or perhaps suppress the expression of genes that should be active). That is where X-chromosome skewness might be pertinent to to those with PWS due to UPD.

The following study investigated the occurrence of extreme XCI skewness in women who have had repeated spontaneous abortions (RSA). The researchers found "a significant excess of trisomic losses" among the women who had RSA with skewed XCI. Remember that the previous study describes PWS due to UPD as the result of "trisomy rescue", that is, an attempt to correct an otherwise fatal trisomy 15 by discarding one of the extra chromosomes; unfortunately the chromosome 15 that is discarded is the one from the father. As most of the literature notes, the above study describes trisomy 15 as being "associated with advanced maternal age." However, the study below might provide an alternative explanation (aside from rotten luck) for why those with PWS due to UPD might have been a trisomy 15 rescue, that is, there might be some relationship between XCI skewness in the mother and a trisomic embryo.

There's also an interesting study of XCI skewness in five familial cases of Rett syndrome, a genetic neurodevelopmental disorder that only affects girls. 99.5% of Rett syndrome cases are sporadic and mutations of the MECP2 gene are present in approximately 70-80% of the sporadic cases. In this study, mutation of the MECP2 gene was present in only one of the families. In the other four families, all of the mothers had 100% XCI skewness, as did six out of the eight girls with Rett syndrome. Interestingly, it was the paternally inherited X chromosome which was active in the girls with XCI skewness.