Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary neuromuscular disorder of unknown cause, characterized by an insidious onset and progressive course. It has been causally related to deletions of tandemly arrayed 3.3 kb repeat units (D4Z4) on chromosome 4q35 possibly affecting expression of nearby genes by a process analogous to position effect variegation (PEV). Interestingly, we observed over-expression of 4q35 genes in FSHD muscles. We discovered that HMG-2, a non-histone nuclear protein involved in heterochromatin formation, is specifically associated to a 27 bp element within D4Z4. We demonstrated that HMG-2 mediates gene silencing at 4q35 and its removal increases gene expression levels, explaining the observed over-expression of those genes in FSHD dystrophic muscles. Our experiments suggest that D4Z4 maintains 4q35 silencing by interacting with a transcriptional repressive complex. It is thus plausible that reduction of repeat number to a critical threshold might induce the over-expression of proximal genes and trigger FSHD pathogenesis. The long term of our studies is to elucidate the FSHD pathogenic process through the analysis of the molecular events occurring at D4Z4. To this aim we will characterize the D4Z4 repressing complex through biochemical purification and functional analysis. We will investigate the effects of D4Z4 deletion on 4q35 gene expression in normal and affected muscle tissues. We expect this analysis to provide a number of genes specifically deregulated in FSHD. Subsequently we will analyze the biological functions of candidate genes in appropriate model organisms. Silencing at 4q35 might also be hampered by abnormalities of repressing complex proteins. Therefore it is possible that non-4q35 FSHD cases might be related to mutations of genes coding those proteins. To this aim, we will screen for mutations in candidate genes all the myopathic individuals referred us for FSHD in which no D4Z4 deletions were detected. Our studies will provide relevant information to understand the molecular basis of FSHD and to develop effective therapeutic strategies.
| Tupler, R; Gabellini, D (2004) Molecular basis of facioscapulohumeral muscular dystrophy. Cell Mol Life Sci 61:557-66 |
| Gabellini, Davide; Green, Michael R; Tupler, Rossella (2004) When enough is enough: genetic diseases associated with transcriptional derepression. Curr Opin Genet Dev 14:301-7 |
| Gabellini, Davide; Tupler, Rossella; Green, Michael R (2003) Transcriptional derepression as a cause of genetic diseases. Curr Opin Genet Dev 13:239-45 |
| Gabellini, Davide; Green, Michael R; Tupler, Rossella (2002) Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110:339-48 |
