Progress Update: Mutations in genes that modify DNA packaging result in FSHD type 2

PI: Daniel G. Miller MD PhD

Daniel G. Miller MD PhD
Daniel G. Miller MD PhD

Friends of FSH 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. Silvère 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.

Dr. Silvère M. van der Maarel
Dr. Silvère M. van der Maarel

Epigenetics 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 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-sponsored scientists Dr. Silvère 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 sponsored projects.

See also the Nature publication Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.

See also 2009 year 2 grant for continuing research to Daniel Miller.

See also the news release by the University of Washington Mutations in genes that modify DNA packaging result in form of muscular dystrophy.