Monday, November 12, 2012

Mutations in genes that modify DNA packaging result in Facioscapulohumeral Muscular Dystrophy type 2.

Friends of FSHD Research has helped fund another ground breaking project that has shed new light on the mechanism of muscle damage in Facioscapulohumeral Muscular Dystrophy, and suggests new targets for treatment.

In today’s issue of Nature Genetics, Dr. Daniel G. Miller and Dr. Silvere M. van der Maarel of Leiden University in The Netherlands, along with an international team, report their latest findings that expand the role of epigenetic modifications in causing the disease. 

Epigenetic s refers to mechanisms that influence how the genome is regulated and how, where and when genes act -- all without altering the underlying DNA sequence.   The flexibility of DNA packaging – its wrapping, which can be tightened and loosened, and its chemical tags – is one of the epigenetic forces on the genome. This packaging is called the chromatin structure and is one way specialized cells such as those in our muscles allow groups of genes to be shut off, or be available for expression.

People with FSHD, usually have a deletion of genetic material that reduces the number of copies of a repeated DNA sequence arrayed on chromosome 4. In a previous study let by Dr. Stephen Tapscott, Friends-sponsored Scientists showed that the genetic deletions in FSHD somehow caused an epigenetic change – an alteration in one of the mechanisms that control a gene’s activity.  The relaxation of the tightly wound chromatin structure allowed the otherwise sealed code in the gene to be read and the toxic DUX4 to be produced in skeletal muscle. Thus the muscle-toxic DUX4 genes within each repeat become inappropriately activated in the wrong tissue at the wrong time causing the symptoms of the disease. 

“Our study builds on this model and identifies a new mechanism that allows this relaxation and DUX4 production to occur. Production of DUX4 in muscle cells can be viewed as a molecular switch. We’ve discovered that the switch that turns on DUX4 expression can be activated in different ways but the mechanism of muscle destruction by DUX4 remains the same. Identifying different ways the switch can be activated is a crucial step toward therapy development because it allows us to apply multiple and different strategies to prevent activation of the switch.”  Miller said.

Five percent of FSHD-affected individuals have array lengths, longer than 10 copies (the threshold for chromatin relaxation), of the DNA sequence in question making them appear to lack the genetic mutation that normally causes FSHD.  However, these unusual individuals lacked repression of DUX4 code-reading in their skeletal muscle cells because of a mechanism other than copy number.

“Breakthroughs in scientific discovery are often achieved by studying individuals with unusual disease presentations,” Miller said. In a multi-institutional collaborative effort the researchers identified individuals without the usual FSHD-disease causing DNA deletion but who still lacked repression of the DUX4 code reading.

Dr. Rabi Tawil at the University of Rochester made the clinical diagnosis in these people and established cultures of muscle cells from biopsies.  Dr. Richard Lemmers working in van der Maarel’s laboratory demonstrated that the chromatin structure was relaxed despite a normal number of repeat units on chromosome 4. With the help of Dr. Michael Bamshad, UW professor of pediatrics, and Dr. Deborah Nickerson, UW professor of genome sciences, Dr. Daniel Miller and his group sequenced and analyzed the protein coding portions of the genomes of individuals with FSHD caused by this uncommon mechanism.
The researchers discovered that these individuals had causative mutations in the Structural Maintenance of Chromosomes Hinge Domain 1 gene located on chromosome 18. Mutations in this gene cause decreased levels of the SMCHD1 protein and result in relaxation of the chromatin structure surrounding the muscle cells’ DNA allowing toxic DUX4 to be generated from chromosome 4.

Understanding the FSHD-causing mechanism of SMCHD1 mutations, Miller said, suggests ideas for therapeutic strategies to suppress the production of the muscle-damaging DUX4 and for treatments for the more common forms of FSHD.

This study would not have been possible without the support of Friends of FSH Research. Friends of FSH Research has sponsored Dr. Daniel Miller since he began working on FSHD in 2006. Dr Stephen Tapscott leads a multi-institutional program project to study FSHD mechanisms and pathology. The NIH funded project includes subprojects by  Friends of FSH Research’s sponsored scientists Dr. Silvere van der Maarel,  Dr. Rabi Tawil, Dr. Galina Filippova and Dr. Daniel Miller and the award of NIH funds for this project can be largely attributed to preliminary data generated by Friends of FSH Research’s sponsored projects.

Friends of FSH Research is a 501(3)(c) non-profit organization whose  mission is to stimulate and fund FSH Muscular Dystrophy research in hopes of finding a treatment or cure for this progressively, disabling condition. Friends of FSH Research  relies upon donations and their annual charity gala, learn more or make a donation go to

Thursday, July 26, 2012

Platform development for candidate drug screening for FSHD

Platform development for candidate drug screening for FSHD: Miller Lab News Story

The Miller Lab has made exciting progress in the development of a platform for screening genes and compounds with activities that affect FSHD-specific pathogenic processes. This platform (developed using funds provided by The Friends of FSH Research and largely orchestrated by FSHD-Research Scholar Dr. Gregory Block) allows muscle cells to be cultured for long periods of time. Most cells when cultured outside of the body have a limited number of cell divisions before they simply stop dividing,  however when expression of the CDK4 and Telomerase genes are “forced” in these cells, they continue to divide as if they had just been removed from someone’s muscle, a finding initially published by FSHD-researcher Dr. Gillian Butler-Browne. The improved longevity allows for careful study of a number of different characteristics in the same cells, and removes some of the experimental variability that is seen when comparing cells that have been allowed to divide for different lengths of time. Most significantly, we have optimized conditions that reveal FSHD-specific differences when cells from FSHD-affected individuals are compared to un-affected control individuals. While this may seem obvious, FSHD researchers have been plagued by the somewhat normal growth, differentiation, and lifespan of FSHD muscle cells, and the lack of physical differences in these cells when their growth characteristics are compared to cells derived from biopsies of normal muscles. Putting these two findings together will allow us to begin to efficiently search for genes and molecules that specifically prevent FSHD-cells from becoming sick. We are excited about the prospects for identification of drug targets that may be useful for developing treatments that slow or eliminate the muscle loss in FSHD.  

Monday, April 16, 2012

New "DNA Combing" Test for FSHD

Biotech company Genomic Vision just announced the release to market of a new method of testing for FSHD. The test uses molecular combing technology that stretches DNA and affixes it to a treated glass surface. The DNA can then be analyzed using FSHD-specific software.

"Current diagnostic methods are laborious and provide results that are difficult to interpret," says Dr. Pierre Walrafen, project manager at Genomic Vision.

The methods Dr. Walrafen refers to are less accurate owing to the complications inherent in the causes of FSHD, and the new test will hopefully improve accuracy and effectiveness in testing for FSHD.

The Timone hospital in Marseille, France, has adopted the technology for regular use--an estimated 300 to 500 patients per year. Prof. Clemens Muller-Reible at the human genetics institute in the Biology Center of the University of Wurzburg is also deploying the method as a beta test.