In a paper published in the journal Nature, Davide Gabellini et al. at the University of Massachusetts, USA, and at univerisites in Pavia, Milano and Modena describe the successful generation of a mouse model which shows a similar disease pattern to patients with facioscapulohumeral muscular dystrophy (FSH). The analysis of this mouse model has not only helped to identify a gene involved in the pathology of the disease, but might also provide essential knowledge to help develop and evaluate potential approaches to treatments.
Facioscapulohumeral muscular dystrophy (FSH) is the third most common inherited muscular dystrophy and affects approximately one in every 20,000 people in Britain. The disease is characterized by progressive weakness and wasting of facial, shoulder and upper-arm muscles. In most of the familial cases, FSH is caused by a deletion of part of chromosome 4 and the extent of the deletion correlates with the severity of the symptoms.
Previous studies revealed that the deleted DNA on chromosome 4 does not code for a gene, a discovery that has made it extremely difficult to find an explanation for the underlying molecular defect. Instead, the deletion comprises repeating blocks of DNA with the same sequence – called tandem repeat units. However, in the vicinity of these tandem repeat units researchers identified three genes that are shown to be abnormally active in patients with FSH. Hence, the hypothesis was that the tandem repeat units interact somehow with these genes and regulate their activity. If the tandem repeats are not present the genes run riot and produce far too much protein – a situation described as overexpression. But, up until now, the scientists did not know which one of those genes might cause the muscle wasting associated with FSH.
In this paper, Gabellini et al. report the results of experiments in which they add the three human genes separately into the genome of mice – called transgenic mice – and screen the mice for symptoms that are seen in FSH. They discovered that one gene alone, termed FRG1, was implicated in the pathology of FSH. It causes the muscles to waste and weaken and the mice also show kyphosis, the typical curvature of the spine. First analysis into the function of the gene shows that it is involved in the maturation of proteins which are specifically required for normal muscle function.
These results are of particular importance because the generation and analysis of this animal model did not only contribute to the identification of a gene responsible for FSH, but will provide further insight into the molecular basis and pathogenesis of the disease. The findings might also present the basis for the development and evaluation of successful treatment strategies.
The article (Nature, Vol. 439, 973-977; 2006) is in technical language and is not freely available.
More information about FSH
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