Thursday, December 16, 2010

Major breakthrough in muscular dystrophy research

Major breakthrough in muscular dystrophy research

It’s often said in research circles that many pairs of eyes are better than just one set when it comes to looking at complex problems.

And at the Hutchinson Center, that kind of collaboration reaches across the globe—often leading to groundbreaking results. Such is the case with the latest news on muscular dystrophy, a disease that has vexed the scientific community for decades.

Researchers have known for 20 years that a genetic mutation is present in people with a common form of muscular dystrophy known as facioscapulohumeral dystrophy, or FSHD, a condition characterized by progressive wasting of muscles in the upper body.

People affected by FSHD share a gene called DUX4 that produces a protein toxic to muscle cells. However, researchers had not been able to explain what caused DUX4 to mutate and create the toxic protein.

Now, they think they have found the key that turns the process on. This summer, an international team—with a Hutchinson Center researcher in a pivotal role—identified a DNA sequence that causes DUX4 to be more active. They now believe that two distinct genetic changes on chromosome 4 must be present to cause FSHD.

“In contrast to most genetic diseases, knowledge of the genetic mutation did not explain the cause of the disease,” said Dr. Stephen Tapscott, an expert in neurogenetics and neuromuscular disease at the Hutchinson Center, and one of the co-authors of the study.

Thanks to these findings, researchers hope it will become easier to diagnose the disease and predict in people showing no symptoms, who will develop it. Currently, FSHD affects 300,000 people worldwide. The latest research also is likely to open the door to new therapies.

“The progress was made possible by an unusual degree of collaboration and data-sharing among the individual groups,” said Tapscott, who was one of several researchers who participated in the study.

(note: Friends of FSH Research launched Dr. Tapscott and the work at Fred Hutch through a pilot grant given in 2006 and other supportive funding through 2010)

Tuesday, December 14, 2010

FSHD: copy number variations on the theme of muscular dystrophy — JCB

FSHD: Copy Number Variations on the Theme of Muscular Dystrophy
  1. Daphne Selvaggia Cabianca1,2 and
  2. Davide Gabellini2

In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD.

(click on title link to read entire report)


Recent studies suggest that copy number variations (CNVs) are important for human phenotypic diversity and disease susceptibility. DNA repeats account for 55% of the human genome and a significant fraction of CNVs.
FSHD is an important pathology caused by CNVs of D4Z4 repeats. It is an extremely complicated and fascinating disease, and research into this topic is revealing much about the functional organization of our genome.
An increasing amount of evidence suggests that the 4q35 macrosatellite repeat D4Z4 plays a crucial role in the chromosomal organization of the FSHD region. There is a general consensus that the D4Z4 deletion in FSHD leads to epigenetic alterations that affect the expression profiles of genes within the FSHD region. Unfortunately, despite considerable effort, almost 20 years after the identification of the genetic defect underlying the disease, the causative FSHD gene(s) remains unknown, and no effective treatments for FSHD are currently available.
The heterogeneity in disease manifestation probably reflects heterogeneity in gene expression in FSHD. An interesting possibility, therefore, is that the complexity of FSHD could be explained by considering it to be a contiguous gene syndrome, where the epigenetic alteration of DUX4, FRG1, and other potential genes collaborate to determine the final phenotype. Finally, because DUX4 behaves as a transcriptional activator (Dixit et al., 2007), it could play a direct role in transcriptional overexpression of the other 4q35 genes, providing a unifying model for the molecular mechanism of the disease.