Tapscott team finds two genetic flaws fuel form of muscular dystrophy

An international research team co-led by Fred Hutch's Dr. Stephen Tapscott has identified two genetic factors behind the third most common form of muscular dystrophy. The findings, published online Nov. 11 in Nature Genetics, represent the latest in the team's series of groundbreaking discoveries begun in 2010 regarding the genetic causes of facioscapulohumeral muscular dystrophy, or FSHD.

The team discovered that a rare variant of FSHD, called type 2, which accounts for about 5 percent of cases, is caused by two genetic mutations that together cause the production of muscle-damaging toxins responsible for causing symptoms of this progressive muscle disease.

Specifically, the researchers found that a combination of genetic variants on chromosomes 4 (called DUX4) and 18 (called SMCHD1) can cause type 2 FSHD. The research team first described the DUX4 variant in 2010 as a mechanism behind the more common type 1 version of muscular dystrophy.

Advances in DNA sequencing

"Many diseases caused by a single gene mutation have been identified during the last several decades, but it has been more difficult to identify the genetic basis of diseases that are caused by the intersection of multiple genetic flaws," said the Human Biology Division's Tapscott. "Recent advances in DNA sequencing made this study possible, and it is likely that other diseases caused by the inheritance of multiple genetic variants will be identified in the coming years."

Understanding the genetic mechanisms of type 2 FSHD could lead to new biomarker-based tests for diagnosing the disease and could lead to the development of future treatments, Tapscott said.

FSHD affects about half a million people worldwide. Symptoms usually first appear around age 20 and are characterized by a progressive, gradual loss of muscle strength, particularly in the upper body.

In addition to Tapscott and his lab colleague Dr. Galina Filippova, other key members of the research team included Dr. Daniel Miller, University of Washington; Dr. Rabi Tawil, Rochester Medical Center; and Dr. Silväre van der Maarel, Leiden University Medical Center, Netherlands; plus investigators from Raboud University Nijmegen Medical Centre in the Netherlands and France's Nice University Hospital.

Funding for the research came from multiple institutions at the National Institutes of Health (National Institute of Neurological Disorders and Stroke, Clinical and Translational Science Awards Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Human Genome Research Institute and the National Genetics Institute), Friends of FSH Research, the Muscular Dystrophy Association, and the University of Rochester Medical Center Fields Center for FSHD and Neuromuscular Research.