Women and Duchenne theme continued with another paper trying to elucidate why some female carriers have symptoms and others have not. Today’s pick is from BMC medical genetics by Brioschi et al from Alessandra Ferlini’s group. Doi 10.1186/1471-2350-13-73
Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype
Authors introduce that it makes sense that some women have Duchenne, e.g. translocation mutations (see Sept 1 thread), or women with Turner syndrome and a dystrophin mutation (Turner patients have only 1 X-chromosome), or women who have two mutated dystrophin genes.
However, carriers have one functional and one mutated dystrophin gene. Authors wanted to elucidate why some carriers manifest symptoms, while others do not. They studied 7 manifesting and 11 non-manifesting carriers.
All 18 women had elevated CK levels, while the 7 manifesting carriers also had muscle weakness and pain with an age of onset of 2-43 years. None of the 18 women had heart pathology.
Staining of muscle biopsies showed a mosaic dystrophin pattern for both manifesting and non-manifesting carriers as well as signs of muscle damage and regeneration.
Authors then looked at X-inactivation patterns in the muscle biopsy. They used a proxy marker for this, the androgen gene (also located on the X-chromosome). In addition, they studied how much dystrophin was expressed from each of the two genes (so mutated and functional transcripts).
Interestingly, there was little correlation between X-inactivation and how much dystrophin was expressed from each gene. This suggests that skewed X-inactivation is not a likely cause of manifesting symptoms for carriers.
Authors note that for the 1 patient with the most severe symptoms, dystrophin levels were very low, while they were higher for an asymptomatic carrier. However, they performed this analysis only for these 2 individuals so it is premature to really draw strong conclusions.
It is good that authors looked at X-inactivation patters in muscle rather than blood (as is often done). However, the pattern in one piece of one muscle may still not be reflective of all the muscles. There is no way around this problem so authors did as well as they could.
Unfortunately, while the paper reveals that skewed X-inactivation is likely NOT to underly the manifesting of symptoms for patients, it does not reveal what IS the cause. Sadly, this is still unknown.