January 2, 2008

Overproduction of Heart Protein Implicated in Myotonic Dystrophy

Overproduction of a protein crucial for the development of the heart is yet another result of the genetic defect that underlies type 1 myotonic dystrophy (MMD1), MDA research grantees report.

Since the mid-1990s, MDA-supported investigators have been among the many researchers attempting to sort out why the MMD1 genetic defect -- an extra stretch of DNA on chromosome 19 that leads to excess RNA in the cell nucleus -- causes so many serious disease symptoms.

In recent years, researchers have identified several mechanisms, including defects in a process called RNA splicing, that result from the extra RNA. When errors occur in splicing, which is necessary for proper formation of cellular proteins, malformation of insulin receptors and chloride channels occurs, accounting for some of MMD1’s effects. (See Scientists Fix Muscle Relaxation)

Now, MDA grantee Mani Mahadevan at the University of Virginia in Charlottesville, and colleagues, who published their results online Dec. 16 in Nature Genetics, have added yet another piece to the MMD1 puzzle.

MDA grantee Jack Puymirat at Laval University in Quebec City, and Charles Thornton, co-director of the MDA clinic at the University of Rochester (N.Y.) Medical Center, also contributed to this study.

By conducting experiments in MMD-affected mice, Mahadevan’s group found that overproduction of NKX2-5, a protein essential for normal heart development that also plays a key role in maintaining regular heartbeats, may account for the heart rhythm abnormalities seen in MMD1.

Surprisingly, in mice and humans with MMD1, they also saw NKX2-5 in skeletal muscles, where it’s not normally found. They say this too may have deleterious consequences.

“I think this study emphasizes that the effects of the toxic RNA in MMD1 are increasingly complex,” said Mahadevan, who will now conduct MDA-supported research on NKX2-5 and its biochemical targets.

“While a justifiable amount of attention has been placed on RNA splicing defects, it’s clear that the toxic RNA has additional deleterious effects that lead to clinically important problems, such as irregular heartbeats in myotonic dystrophy. Treating splicing defects may affect only some aspects of the disease. The root of the problem is still the toxic RNA.”

In the meantime, he said, measuring the NKX2-5 protein in muscle tissue or some of its biochemical effects that show up in the blood may become good diagnostic or prognostic markers that could be used to follow disease progression or response to therapy, although that concept needs further validation in patients.