Cardiovascular Sciences  

1999 Recipient

Myotonic dystrophy: a novel mechanism for regulation of gene expressions at the RNA level

Dr. Lubov Timchenko and Dr. Thomas Cooper's research focuses on myotonic dystrophy, which belongs to a family of human disorders associated with triplet repeat expansions. A major subject of Dr. Timchenko's studies is to elucidate the role of RNA triplet repeat binding proteins in myotonic dystrophy pathogenesis. She proposed a new hypothesis suggesting that myotonic dystrophy pathogenesis is due to alterations in activities of RNA binding proteins. Her laboratory has identified a family of CUG repeat binding proteins that are affected in myotonic dystrophy patients. A major focus of Dr. Cooper's lab is to understand the mechanisms of gene regulation during the normal process of pre-RNA splicing. Some genes express pre-mRNAs that are spliced in multiple ways and express different proteins with diverse functions. His laboratory identified a region within a subclass of pre-mRNAs that is required for a muscle-specific splicing pattern. One of the unique features of this region is the presence of CUG repeats. This suggested a link with Dr. Timchenko's CUG repeat binding proteins. Drs. Cooper and Timchenko demonstrated that one CUG-binding protein that is affected in myotonic dystrophy (called CUG-BP1) binds to the muscle-specific splicing element and regulates splicing of the cardiac troponin T (cTNT) pre-mRNA. They found that splicing of the cTNT pre-mRNA is abnormal in myotonic dystrophy cells, consistent with abnormal function of CUG-BP1. CUG-BP1 is likely to regulate post-transcriptional processing of many genes. It is the misexpression of these genes that is likely to be a major cause of myotonic dystrophy pathogenesis.

Dr. Cooper and Timchenko’s nomination was based on the following publications:

Roberts R, Timchenko NA, Miller JW, Reddy S, Caskey CT, Swanson MS, Timchenko LT. Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice.Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13221-6.

Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998 May 1;280(5364):737-41.

Cooper TA. Muscle-specific splicing of a heterologous exon mediated by a single muscle-specific splicing enhancer from the cardiac troponin T gene. Mol Cell Biol. 1998 Aug;18(8):4519-25.

Lu X, Timchenko NA, Timchenko LT. Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum Mol Genet. 1999 Jan;8(1):53-60.

Timchenko LT. Myotonic dystrophy: the role of RNA CUG triplet repeats. Am J Hum Genet. 1999 Feb;64(2):360-4. Review. No abstract available.