Random X-Inactivation and Duchenne

Question

I'm reading about X-inactivation and I can't reconcile some things with it being truly random. In only a small percentage of female carriers Duchenne's will be expressed. But if this was truly random, wouldn't 50% of female carriers expressing the disease? As one of the X-chromosomes is silenced at random, this seems sort of contradictory. Then, in females that do express the disease phenotype it's because of non-random X-inactivation. For me, this sounds like it's the other way around, so clearly I'm not up to speed and am in need of a bit of clarification on the subject.

Answer 1

Duchenne muscular dystrophy (DMD) is caused by the body's inability to make the protein dystrophin, which is needed for proper muscle function (1, 2). In an individual carrier, half of the cells that would normally make dystrophin cannot, but the other half still can. This leads to two explanations (AFAIK) for why carriers do not express DMD:

1. The cells that can make dystrophin make twice as much, so the total amount produced is the same as a normal individual.
2. Only half as much dystrophin is produced, but that is enough to prevent symptoms from manifesting.

This is actually the stock explanation for why female carriers exist for X-linked recessive diseases. You can substitute 'DND' and 'dystrophin' with another X-linked recessive disease and the associated protien (e.g. 'hemophilia' and 'factor 8 or 9') and it would still be mostly true.

I say mostly true because DMD is actually an unusual. Its carriers do sometimes exhibit symptoms (3, 4). Different studies give different rates for how often this happens, but the NIH says it is about 20%.

EDIT: I am still a little unclear on what your asking, but I think you are confused about why any carriers for Duchenne express the disease. The answer to that is a phenomena called skewed X-inactivation, which is when either the paternal or maternal X chromosome is inactivated and turned into a Barr body more often than the other. This can happen for 2 reasons:

1. Primary: When Barr bodies are forming, the paternal or maternal chromosome is selected more than 50% of the time.
2. Secondary: After Barr bodies form, cells with the paternal chromosome active reproduce less than cells with the maternal chromosome active, or vice versa.

Both types of skewing can be happen for genetic causes (e.g. the Xce locus in mice can cause primary inactivation) or stochastic causes (i.e. by pure chance some people will have unlikely things happen to them).

I spent the last few hours reading up on which type happens specifically during Duchenne and I am still not 100% sure. What I am confident about is that carriers for Duchenne can have a translocation, which causes the skewed X-inactivation and therefor symptoms in carriers:

A few cases of translocations involving DMD have been reported22; these translocations will cause DMD in both males and females, the latter owing to non-random X-inactivation of the unaffected X chromosome. In these cases, cells with inactivation of the mutated X chromosome (cells that could, in theory, produce dystrophin) are not viable owing to the inactivation effect of the chromosomal translocation on the autosome. Only the cells where the unaffected X chromosome is inactivated will be viable. However, these will not produce dystrophin owing to the chromosomal translocation affecting DMD. Therefore, females with these translocations are unable to produce any dystrophin.

What I cannot figure out is if the translocation happens on the chromosome with the functioning DMD gene or the chromosome with the defective DMD gene.