Spotlight on Research 2011

January 2011 (historical)

Genetic Discovery Improves Understanding of FSH Muscular Dystrophy Cause

A new study supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has found that two separate genetic arrangements – both on chromosome 4 – are needed to start the disease process in facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy. The finding brings scientists a step closer to understanding the cause of FSHD, knowledge that would allow researchers to begin designing strategies that could eventually lead to treatments.

The study’s international team of investigators, including NIAMS-supported scientist Stephen Tapscott, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle, discovered that a repeating DNA unit containing a gene called DUX4 interacts with adjacent genetic variations to determine whether a person will have FSHD, which causes progressive muscle wasting in the upper body.

In the early 1990s, scientists found that FSHD is associated with a shortened DNA sequence at the end of chromosome 4, called a tandem repeat array. Normally, that region of the chromosome contains 10 to 100 repeating units of DNA. They found in most people with FSHD the array is smaller, with fewer than 10 repeats. Within each repeating unit is the DUX4 gene, which encodes a protein that harms muscle cells. Later research, however, showed that this genetic variation alone could not cause FSHD – something else was needed to trigger the disease’s muscle damage. The new research, reported in the journal Science, demonstrates that the smaller array only causes FSHD if there is an additional DNA mutation in the same region of chromosome 4 that allows DUX4’s RNA to stabilize and the protein to accumulate to disease-causing levels.

People with FSHD have chromosome variations that add a trailing segment called a poly(A) tail to the RNA. With the poly(A) tail, the RNA is more stable and accumulates to detectable levels. Previous studies have shown that expression of the DUX4 gene in muscle cells causes defects in cellular growth, development and the ability to maintain internal stability that are consistent. In a subsequent publication, Dr. Tapscott’s research group demonstrated a full-length DUX4 RNA with a poly(A) tail expressed in skeletal muscle from FSHD patients, but not in muscle from control subjects.

While further research is needed to confirm and better understand the implications of their findings, the scientists say that their results may make it easier for doctors to diagnose FSHD in people with muscular dystrophy symptoms. In addition, for those in affected families who have not yet experienced symptoms, the results will help predict who may develop the disease. The study also has important implications for treatment. Presently, treatment for FSHD is limited to physical therapy, orthopaedic procedures and drugs that may help with specific symptoms in some patients. Although there are no treatments for the progressive muscle weakness and wasting characteristic of FSHD, the new findings point to potential targets for treating the disease in novel ways that address the causes.

Support for the study was provided by a number of other organizations, including the National Institute of Neurological Disorders and Stroke (NINDS), the FSH Society, the Fields Center for FSHD and Neuromuscular Research, the Pacific Northwest Friends of FSH Research and the Muscular Dystrophy Association.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at


Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010 Sep 24;329(5999):1650-3.