Myotonic dystrophy is a disorder that affects multiple body systems. It is characterized by progressive muscle weakness, cardiomyopathy and arrhythmias, cataracts, and abnormalities in brain and endocrine function, including mental retardation. There is a wide variation in the severity of symptoms between patients, although the condition is generally more severe and/or appears at an earlier age in later generations of a family that is affected.

Myotonic dystrophy is caused by a mutation in a gene called DMPK. At one end of this gene there is a stretch of DNA (deoxyribonucleic acid) containing a group of three nucleotides (each designated C, T, and G) that is repeated over and over again. Myotonic dystrophy occurs when the number of these CTG "trinucleotide repeats" in this region increases to greater than a certain amount. When a messenger RNA (ribonucleic acid) copy is made of this gene as part of the normal process of gene expression, then RNA accumulates in the cell that contains an excessive number of CUG trinucleotide repeats. (The "U" nucleotide in RNA is equivalent to the "T" nucleotide in DNA.) The accumulation of CUG repeat RNA then leads to overactivity of a protein that processes messenger RNA, called "CUG-BP." As a consequence, other RNA molecules are incorrectly modified, which leads to a disruption in the protein-manufacturing process for those genes. Some of the RNA molecules that are affected by CUG-BP come from genes that are involved in skeletal and heart muscle, and in insulin regulation, which probably explains the unusual form of insulin resistance and myotonia that are seen in myotonic dystrophy. Presumably the disruption of other genes would explain the variety of symptoms seen in this disorder. It is not currently known what might cause the mental retardation that is seen in the more severe cases.

If a DNA-copying error during the production of eggs or sperm causes the CTG trinucleotide repeat region to become larger, then the region becomes more unstable and further errors are likely. This explains progressive expansion of the region through subsequent generations of a family. Larger expansions result in more severe clinical symptoms.

Ongoing research at the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center:

Further understanding of the disease
The CUG-BP protein that cuts and splices messenger RNA is one of a family of six "CELF" proteins that have similar functions. Investigators are studying the entire family of CELF proteins to determine where and when they are expressed, how they are activated by the presence of excessive CUG trinucleotide repeats, and what genes are affected by CELF proteins that might be directly related to the occurrence of myotonic dystrophy symptoms. Laboratory-grown cells and genetically altered mice that produce RNA with expanded CUG regions are being established, which will provide useful biological systems for study of the effects of trinucleotide repeat expansion.

During the normal process of generating cells that are specialized for particular functions (i.e., "differentiation"), these cells often lose their ability to reproduce. Studies at Baylor College of Medicine have shown that a significant portion of skeletal muscle cells from myotonic dystrophy patients keep their ability to proliferate and fail to differentiate properly. In addition, the CUG-BP splicing protein stays in the cell nucleus, instead of passing to the cytoplasm as it normally does. A hypothesis being tested is that CUG-BP normally activates a protein called p21 that is involved in halting cell division as the cells complete their differentiation into a specialized state. If, in myotonic dystrophy, the CUG-BP protein remains trapped in the cell nucleus, then it fails to activate p21, and the cell therefore continues to reproduce. Various experiments will be performed to test this hypothesis.

Work towards therapy
The cell and mouse lines described above that are designed to produce expanded CUG regions in RNA can be used as experimental systems to test therapeutic options for myotonic dystrophy.

Baylor investigators working on Myotonic dystrophy:

Baylor MRDDRC projects associated with Myotonic dystrophy :

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Myotonic dystrophy resources:

Organizations: