New insights into cardiac defects in Myotonic Dystrophy Type 1

People with Myotonic Dystrophy Type 1 (DM1), the most common adult-onset form of muscular dystrophy, progressively lose muscle mass and strength in their lower legs, hands, neck and face. The effects of the condition extend to the cardiac and central nervous systems and the gastrointestinal organs.

The laboratory of Dr. Thomas A. Cooper, professor of pathology and immunology, of molecular and cellular biology and of molecular physiology and biophysics at Baylor College of Medicine, has long been improving our understanding of DM1. In the current study published in Human Molecular Genetics, Cooper and his colleagues tested a strategy to improve heart defects associated with the disease and uncovered an unexpected new insight into the condition.

Cardiac problems affect 50% of DM1 patients and are the second leading cause of mortality in affected individuals, after respiratory insufficiency resulting from skeletal muscle wasting.

"DM1 affects various aspects of cardiac function, but primarily involves conduction delays and arrhythmias, problems with the electrical system of the heart," said Cooper, who also is the S. Donald Greenberg and R. Clarence and Irene H. Fulbright Professor and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "Our lab has developed a mouse model that replicates many of the cardiac characteristics observed in the human disease. In this model we tested an approach to reverse the cardiac problems of the condition."

The widespread domino effect of one mutation

DM1 is caused by a mutation in the DMPK gene that makes it longer by adding extra three-DNA building block repeats (CTG). While the unaffected population carries 5 to 37 repeats, people with the condition have 50 to 3000 CTG repeats.

Carrying this mutated DMPK gene has a domino effect that alters the way hundreds of other genes are normally expressed during development. SCN5A in the heart is one of these genes. The fetal heart predominantly expresses a fetal form of protein SCN5A. As the individual develops, the heart produces less of the fetal form and the adult form of the protein becomes predominant.

In DM1, the fetal-to-adult transition of SCN5A is altered – the fetal SCN5A protein is significantly increased in the adult DM1 heart. The slower electrical activity associated with the fetal SCN5A form is relevant to DM1, as we and others have shown. The studies demonstrated that increased levels of the fetal SCN5A resulted in cardiac conduction deficits consistent with DM1. SCN5A is a primary candidate for arrythmias in this condition."

Dr. Larissa Nitschke, first author, postdoctoral associate in the Cooper lab

The goal in this study was to determine whether reducing the expression of fetal SCN5A protein in the adult heart in a mouse model of DM1 would reverse arrythmias.

"We used CRISPR/Cas9, a laboratory technique that allowed us to delete the gene for the fetal form of Scn5a from the mouse genome. The resulting mice exclusively expressed the adult Scn5a form. "To our surprise, mice lacking the fetal form of Scn5a did not improve conduction delays and structural and functional heart deficits, indicating that this strategy is not sufficient to correct the heart defects caused by the expression of the extra CUG repeats," Cooper said.

"We were intrigued by this unexpected finding, so we continued investigating and discovered that, both in mice and patients with DM1, the levels of adult SCN5A were about half of what is present in individuals without the disease," Nitschke said. "Patients are not only expressing higher levels of the fetal form relative to the normal adult form, but also their levels of the adult form are half of those of a person without the condition."

"Our findings have provided a deeper understanding of DM1. They show that correcting the increased expression of fetal Scn5a is not sufficient to improve DM1 cardiac alterations and suggest that the reduction of the levels of adult SCN5A and maybe other proteins may contribute to the cardiac defects in DM1," Cooper said.

The researchers are now testing whether increasing SCN5A in the heart model will reduce the cardiac problems of the condition.

Rong-Chi Hu and Andrew N. Miller, also at Baylor, contributed to this work.

This work was supported by the National Institutes of Health grants (R01HL147020, R01AR082852, F32AR083267, P30CA125123, S10OD032380, UM1HG006348 and R01DK114356) and a postdoctoral fellowship from the Myotonic Dystrophy Foundation.