Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary myopathies, with an incidence of 1 in 20,000. Insidious onset and progressive course characterize it. The disease has been causally related to deletion of tandemly arrayed 3.3 kb repeat units (D4Z4) on chromosome 4q35 possibly affecting chromatin organization and nearby gene expression. Consistently, we have observed that a number of genes mapping at 4q35 are over-expressed in the FSHD affected muscle. We have also discovered that within D4Z4 unit a 27 bp DNA element has a protein-binding activity. Through biochemical purification, we have isolated three proteins, YYI, HMGB2, and nucleolin, forming a multi-protein complex that binds D4Z4. We have been also able to demonstrate that this multi-protein complex is involved in silencing of gene located at 4q35. Our data suggest that D4Z4 elements contribute to 4q35 gene silencing through the interaction with a transcriptional repressing complex. We propose that the reduction of D4Z4 tandemly repeated units to a critical threshold might induce the over-expression of 4q35 genes and, as a consequence, trigger FSHD pathogenesis. In this proposal we present an experimental plan to dissect the FSHD pathogenic process through the analysis of the molecular events occurring at D4Z4.
Our aims are: 1. To elucidate the mechanism underlying the control of gene transcription at 4q35. 2. To identify 4q35 genes specifically involved in FSHD pathogenesis. 3. To investigate the role of 4q35 gene over-expression in animal models. In summary our studies on mechanisms controlling gene expression in the FSHD chromosomal region and characterization of 4q35 genes and will provide relevant information to understand the molecular basis of FSHD and to develop effective therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047584-05
Application #
7259390
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Porter, John D
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$348,635
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Scionti, Isabella; Fabbri, Greta; Fiorillo, Chiara et al. (2012) Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling. J Med Genet 49:171-8
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