Final Activity Report Summary - FSHD ANIMAL MODEL (An Animal Model to Develop Therapeutic Strategies for Facioscapulohumeral Muscular Dystrophy, FSHD.)
The goal of this research project was to understand the molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD) in order to develop possible therapeutic approcahes.
FSHD is the third most common muscular dystrophy, for which there is no treatment or cure at present. FSHD is associated with reduction in the number of copies of deoxyribonucleic acid (DNA) on chromosome 4, called D4Z4, which is repeated many times towards the end of the long arm of chromosome 4.
We hypothesised that D4Z4 might control the activity of nearby FSHD genes. We found that there was an increased production of the proteins encoded by the genes close to D4Z4 in FSHD patients. Interestingly, we found that these proteins were over-produced, specifically in the muscles of FSHD patients, explaining the fact that FSHD is primarily a disease of skeletal muscle. More recently, through following the idea of modelling in an animal the same conditions observed in FSHD patients, we generated mice that overproduced the same proteins which were overproduced in the muscles of FSHD patients. We found that mice overproducing a protein called FRG1 displayed several features of FSHD patients. Based on these results, we proposed that it was loss of D4Z4 causing overproduction of FRG1, which in turn led to FSHD.
During the Marie Curie international reintegration grants (IRG) funding period, we performed the following tasks:
1. we understood the molecular mechanism that was responsible for increased production of 4q35 proteins in FSHD
2. we understood the specific processes that went awry in muscles of patients suffering from FSHD
3. we used the FSHD animal model to test possible gene therapy approaches for FSHD.
The results of our research were anticipated to contribute in the development of effective therapeutic approaches for FSHD.
FSHD is the third most common muscular dystrophy, for which there is no treatment or cure at present. FSHD is associated with reduction in the number of copies of deoxyribonucleic acid (DNA) on chromosome 4, called D4Z4, which is repeated many times towards the end of the long arm of chromosome 4.
We hypothesised that D4Z4 might control the activity of nearby FSHD genes. We found that there was an increased production of the proteins encoded by the genes close to D4Z4 in FSHD patients. Interestingly, we found that these proteins were over-produced, specifically in the muscles of FSHD patients, explaining the fact that FSHD is primarily a disease of skeletal muscle. More recently, through following the idea of modelling in an animal the same conditions observed in FSHD patients, we generated mice that overproduced the same proteins which were overproduced in the muscles of FSHD patients. We found that mice overproducing a protein called FRG1 displayed several features of FSHD patients. Based on these results, we proposed that it was loss of D4Z4 causing overproduction of FRG1, which in turn led to FSHD.
During the Marie Curie international reintegration grants (IRG) funding period, we performed the following tasks:
1. we understood the molecular mechanism that was responsible for increased production of 4q35 proteins in FSHD
2. we understood the specific processes that went awry in muscles of patients suffering from FSHD
3. we used the FSHD animal model to test possible gene therapy approaches for FSHD.
The results of our research were anticipated to contribute in the development of effective therapeutic approaches for FSHD.