New Studies Improve Understanding of Myotonic Dystrophy

by Quest Staff on March 1, 2008 - 10:37pm

QUEST Vol. 15, No. 2

Myotonic dystrophy (MMD), a complex disease that results from an expanded and repeated section of DNA on either chromosome 19 (MMD1) or chromosome 3 (MMD2), has long posed a challenge to researchers because of its effects on multiple body systems, its varying degrees of severity and its complex molecular origins.

In both forms of the disease, extra-long strands of genetic material called RNA are made from expanded DNA sections, causing a variety of cellular problems. Recently, scientists have shed light on some of these, particularly in MMD1.

Normal muscle relaxation restored in MMD-affected mice by fixing chloride channels

Researchers at the Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at the University of Rochester (N.Y.) and the University of Florida in Gainesville report that they’ve used a molecular strategy to restore normal muscle relaxation after contraction in mice with a disease resembling MMD1. The Wellstone Center is supported by the U.S. National Institutes of Health and has also received support from MDA.

Charles Thornton, who co-directs the MDA clinic at the University of Rochester Medical Center, led the research team, which published its results online Nov. 15 in the Journal of Clinical Investigation. Maurice Swanson, an MDA grantee at the University of Florida in Gainesville, was also part of this study.

The genetic defect that underlies MMD1 indirectly causes a variety of muscle and other problems, including myotonia, the inability to relax muscles after using them. The direct cause of the myotonia, however, is abnormally constructed cellular tunnels called chloride channels.

Earlier studies have shown that, in MMD1, the expanded section of DNA on chromosome 19 leads to errors in a process called RNA splicing and thereby to faulty construction of the chloride channel and other proteins.

When the research team injected MMD-affected mice with a synthetic compound that corrects the RNA splicing process, they fixed the chloride channels and relieved the myotonia.

Overproduction of heart protein implicated

Overproduction of a protein crucial for the development of the heart should be added to the growing list of effects of the genetic defect that underlies MMD1, MDA research grantees report.

In recent years, researchers have identified several mechanisms, including defects in RNA splicing (see “Normal muscle relaxation”) that result from this defect.

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.

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 at all. 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.

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.

DMPK may warrant closer look

A deficiency of an enzyme known as DMPK (myotonic dystrophy protein kinase) may have more to do with MMD1 than scientists had previously believed, say Perla Kaliman at the Hospital Clinic of Barcelona (Spain) and colleagues in the November issue of PLoS One.

MMD1 results from an expanded stretch of DNA in the gene for DMPK that keeps this protein’s genetic instructions (RNA) from leaving the nucleus of muscle cells. However, almost everyone with MMD1 has one normal and one abnormal DMPK gene, so it’s expected that they manufacture about half the normal amount of DMPK.

Although a deficiency of DMPK causes some cardiac problems, most experts have thought until recently that lack of DMPK wasn’t a very important contributor to the multiple abnormalities seen in MMD1.

Now, Kaliman and colleagues have shown that when mice are bred to produce no DMPK at all, they develop high blood sugar and higher-than-normal levels of circulating insulin, indicating that they have insulin resistance, as do many MMD1 patients.

Further studies are needed to see whether mice with half the normal amount of DMPK have any insulin abnormalities, but the new experiments, added to the older ones showing cardiac defects from lack of DMPK, suggest that a deficiency of DMPK in MMD1 may be worth a closer look.

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