Myotonic Dystrophy Foundation

Anticipation is a word often associated with good things; a word associated with hope and looking forward. But in the upside-down world of myotonic dystrophy, anticipation means that for the next generation and the generations after that, things are likely to get worse. Dr. Carol Wilusz and her research team at Colorado State University are hoping their work in investigating the role messenger RNA stability plays in the pathogenesis of myotonic dystrophy will help take back the word anticipation and give new hope to those diagnosed with this devastating disorder.

Myotonic dystrophy is a genetic disorder that, according to the Myotonic Dystrophy Foundation, affects 1 in 8,000 people worldwide, with 40,000 of those in the United States. The condition has a “dominant” inheritance pattern meaning that a parent with myotonic dystrophy (who may not know they have the condition) has a 50 percent chance of passing it on to their child. Symptoms vary depending on type and age of onset, but can include wasting of muscles, cataracts, heart conduction defects, endocrine changes, club feet, and myotonia (the slowed release of muscles after contraction).

“In certain genes, a small stretch of DNA containing three nucleotides (a triplet) is repeated over and over, “said Dr. Wilusz, an Associate Professor in the Department of Microbiology, Immunology and Pathology. “This repeated DNA structure occurs normally, but when it expands too much it becomes unstable. Type 1 myotonic dystrophy, DM1, is caused by an expanded CTG repeat (the nucleotides cytosine (C), thymine (T), and guanine (G)) that occurs in the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19.”

Dr. Wilusz said that in healthy individuals, there are between five and 37 CTG repeats. In DM1 patient families, the first generation might have between 50 and 100 repeats, the following generation might have between 200 and 500 repeats, and the next generation could have more than 1,000 repeats. This last generation presents with the congenital form of myotonic dystrophy which is the most severe form of the disease. This is the phenomenon of anticipation, as each child will have a larger expansion than their parents, and consequently each generation will have more severe disease.

“We know this is a genetic disorder, but we are trying to better understand the mechanisms,” said Dr. Wilusz. “The repeat is transcribed into the mRNA where it causes retention of the transcript in the nucleus, instead of it moving into the cytoplasm and being expressed. We end up tying one huge knot in the nucleus. One project in our laboratory is focused on learning why the repeat-containing mRNA is not recognized and degraded by cellular surveillance mechanisms. If we can help the cell degrade the toxic transcripts, we could cure the disease.”

CELF1/CUGBP1 is one protein whose expression is dramatically affected in DM1 patients. It is overexpressed by a mechanism that is not yet understood. Dr. Wilusz’ laboratory has conducted research that indicates a mis-expression of CUGBP1 plays an integral role in altering decay of certain mRNAs in DM1 patients. Recent published research demonstrated that CUGBP1 associates with GU-rich elements (the consensus sequence UGUUUGUUUGU) to regulate decay of a wide range of mRNAs including several that are critical for muscle development (http://www.ncbi.nlm.nih.gov/pubmed/20574513).

“We found 880 mRNA genes associated with the CELF1 protein, and some of these may play a role in the failure to renew damaged muscle,” said Dr. Wilusz. “We are trying to understand this better by taking patient cells and immortalizing them, then we will try to determine what CELF1 is doing, look for defects in mRNA stability, and investigate how such defects might contribute to pathogenesis.

“Once we can better describe the pathogenesis of myotonic dystrophy we may be able to identify potential targets for therapies. Right now there is no cure or treatment for myotonic dystrophy, just a few drugs that help relieve some of the symptoms. Ultimately, what we need to do is figure out how to get rid of these repeats, but modulation of CELF1 activity also is a promising therapeutic avenue.”

Dr. Wilusz’ research is funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health), by the College of Veterinary Medicine and Biomedical Sciences’ College Research Council, and by the Myotonic Dystrophy Foundation.

Source: Colorado State University, August 7, 2011