Scientists work out the curious genetics behind common form of muscular dystrophy
A scientific team that included researchers from Europe, the University of Rochester and Seattle has worked out how a curious genetic mutation may cause a common form of muscular dystrophy.
People with the condition, called facioscapulohumeral muscular dystrophy or FSHD, develop muscle weakness starting in face, shoulders and upper arms.
The weakness tends to appear when a person reaches his or her teens, grows more severe with time and can eventually spread to other muscle groups. Severity can range from mild to disabling.
The findings of the new study may someday lead to a treatment for the disease.
Silvère M. van der Maarel, professor of medical epidgenetics at Leiden University Medical Center led the study in collaboration with Dr. Rabi Tawil, M.D. of the University of Rochester Medical Center and Dr. Stephen Tapscott of the Division of Human Biology at the Fred Hutchinson Cancer Research Center. Dr. Daniel Miller of the University of Washington was also on the research team.
The search for the gene
Dr. Stephen Tapscott
Early genetic studies indicated that the gene causing FSHD was located at the end of chromosome 4. But it was not clear exactly where the gene was.
One area of interest was a structure at the end of the chromosome called a macrosatellite repeat array. These arrays are composed of the same sequence of DNA repeated over and over again.
Such arrays occur commonly in our chromosomes, but are usually inactive.
This is because, if there are genes present within the array, the genes are not “expressed”, that is, the proteins the genes code for are not synthesized by the cell.
In the case of the array at the end of chromosome 4, the array usually contains 11 to 100 repeated sequences, and when this is the case, no disease develops.
But when the array is shortened by a mutation so that it contains only 1 to 10 repeats, the disease occurs.
Why this shortening of the array leads to disease, however, was a mystery.
To add to the puzzle, there is a similar array on the end of chromosome 10, but when it is shortened it does not cause disease.
So there was something about chromosome 4 that was key.
Scientists proposed several nearby genes as possible culprits, but none of the genes provided an entirely satisfying solution, says co-author Dr. Tapscott of the Fred Hutchinson Cancer Research Center.
DUX4
There was, however, a gene within the array repeats, called DUX4, and, in a 2007 paper, Dr. Yi-wen Chen of Children’s National Medical Center in Washington, D.C., and colleagues showed that this gene was indeed being expressed in patients with FSHD, Dr. Tapscott says.
The questions, then, were:
- Why did this happen only when the macrosatellite repeat array was limited to 1 to 10 repeats?
- And why only when the array was on chromosome 4 and not chromosome 10?
The key to the puzzle, says Dr. Tapscott, that the last repeat at the end of the array was different from the others. Next to it was the sequence of DNA that coded for a specific string of molecules called a polyadenylation signal.
Such signals are essential to efficient protein synthesis.
The presence of this signal sequence at the end of the array suggested that if the the DUX4 genes in the array could be expressed with the signal attached, the DUX4 protein would be synthesized by the cells.
In the paper in Science , the researchers show is that this indeed appears to be the case.
What appears to be happening is that when the macrosatellite repeat array is shortened it allows the DNA to uncoil in such a way that the genes can be activated and transcribed with the required polyadenylation signal attached.
The reason why shortening of the array on chromosome 10 has no effect is that there are no sequences coding for the polyadenylation signal in the right location nearby.
Just how expression of the DUX4 gene causes FSHD is still not known, says Dr. Tapscott, but one theory is that the DUX4 protein is toxic to the muscle cells.
The new findings provide researchers with model that unifies all the observations about the genetics of FSHD and that should help researchers make progress in their understanding of disease, said Dr. Tapscott.
To learn more:
- Read the Science paper: A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy
- Visit Dr. Tapscott’s lab’s webpage.
- Visit the National Library of Medicine’s MedLine Plus page on muscular dystrophy
Category: Fred Hutchinson Cancer Research Center, Genetics & Birth Defects, Seattle Science
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