By David N. Leff

When is common uncommon?

The commonest inherited muscle disorder in children is Duchenne muscular dystrophy, which afflicts one in 3,000 boy babies born alive in the U.S. The commonest muscle malady in adults is myotonic dystrophy (DM) - which strikes people of both sexes, at an estimated rate of one in 7,400. It currently affects some 40,000 Americans.

What makes DM uncommon is that its progressive muscular pathology is far from the only affliction suffered by its victims. When the neurologist shakes hands with someone suspected of DM, the patient can't let go. His muscles contract firmly, but can't relax. This same hallmark symptom makes it tough for a DM victim to turn a doorknob, grasp a bottle cap or write with pen or pencil.

But those inconveniences are just the most obvious tip of DM's chilling iceberg of symptoms. These can arise at any time in life, with onset of disease up to 50 or 60 years. Premature frontal balding is frequent, as is the lean, elongated look caused by weakness in the facial and temple muscles. Cataracts occur in 90 percent or so. Perhaps 80 percent incur testicular or ovarian atrophy. And there is mental retardation. (See BioWorld Today, May 5, 1998, p. 1.)

More life-threatening, two out of three people with myotonic dystrophy have severely weakened hearts, and respiratory failure or cardiac arrest are the main causes of DM death - often before 50 years of age. "The main effect in the heart," observed clinical and research neurologist Charles Thornton, "is on its specialized system for conducting electrical impulses, and regulating the heartbeat - not on the contractile or pumping muscular component.

"A typical age of onset for myotonic dystrophy," Thornton said, "is between 15 and 30 years. But of all human genetic diseases, DM may be the most variable, because the age of onset is really anywhere from prenatal to after 50." He made the added point that, "Manifestations extend well beyond the muscles, so degeneration of the heart and effects on the brain can be major limitations in people with this disease."

Thornton, an associate professor at the University of Rochester, N.Y., co-directs that institution's Neuromuscular Disease Center. He is senior author of a paper in today's Science, dated Sept. 8, 2000, titled: "Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat."

Mutant Messenger RNA Guilty As Charged

"This work," he told BioWorld Today, "establishes a biologic principle that mutant RNA can have a direct pathogenic effect. It also demonstrates," Thornton added, "that accumulation of this particular mutant RNA in the cell's nucleus interferes in some way with nuclear function. Every other human genetic disease that we know of is caused by abnormalities ultimately in the proteins that the genes code for. A faulty mRNA that actively causes disease seems to go against genetic dogma."

The mutation that causes DM does damage to the myotonic dystrophy-protein kinase gene (DMPK),. which resides on the long arm of human chromosome 19. But quite unlike the usual way that a mutant gene causes disease by the misbehavior in the body of the mutated protein it expresses, the mutated DM gene misbehaves by loose-cannon proliferation of the DNA triplet codon CTG (cytosine-thymidine-guanine) in hundreds, even thousands, of iterations.

Triplet codons also wreak havoc in other neurodegenerative diseases, such as CAG (cytosine-adenine-guanine), which repeats itself out of control in Huntington's chorea.

"The inheritance pattern of myotonic dystrophy," Thornton pointed out, "is autosomal dominant with a few twists. The twists are that the severity of the disease gets worse in successive generations. A particularly severe form that is often fatal in infants - about 10 percent of myotonic dystrophies - is transmitted only by mothers. This probably relates to differences in the dynamics of the triplet repeat instability in spermatogenesis as compared to oogenesis.

"The mutation," he explained, "is an unstable expansion of CTG repeats, and that instability usually leads to lengthening of the repeat sequence when the mutation is transmitted from one family generation to the next. But the magnitude of that lengthening is somewhat different for generating sperm than it is for generating an ovum."

More than a dozen attempts by scientists the world over to create a transgenic mouse that could faithfully mimic myotonic dystrophy have failed to reproduce the typical muscle manifestations. Here is how Thornton and his co-authors finally succeeded:

"The experiment was fairly simple," he recounted. "We began by inserting an expanded CTG repeat into a human skeletal-muscle actin gene. Then we injected that gene into fertilized mouse eggs. Some of the animals that developed from those eggs had incorporated the gene into their genome, which became highly activated in the muscle cells.

"And the RNA that gene synthesized," Thornton went on, "built up inside the cell nuclei, which led to degeneration in those muscle cells. So, in effect, we were creating a mouse model of the human disease."

The mice duly developed the muscle stiffness that marks DM, and handed the team a surprise "that may have implications for other diseases," Thornton observed. "Normally," he pointed out, "messenger RNA transmits genetic information out of the nucleus into the main parts of the cytoplasm, where its instructions are carried out. That's its only job. In these mice, it seems to stay in the nucleus, doing something entirely different that's harmful."

For Future Therapies, Prospects, Not Promises

This new animal model cleared the way for the Rochester group - and other labs sharing their new DM mice - to tackle three open questions, which they are now pursuing:

¿Why is messenger RNA that has an expanded CUG repeat (the RNA equivalent of DNA's CTG) trapped in the cell nucleus?

¿How does it affect the way that a nucleus functions?

¿How does it affect other mRNA that's been generated in the same nucleus?

Meanwhile, Thornton pointed out, "There isn't an obvious, instant therapeutic implication in this work. However, we remain hopeful that this form of muscular dystrophy will prove to be the most treatable form, because atrophy of muscles - as opposed to their destruction - is potentially reversible. And compared to most other dystrophies, in DM no, essential structural component is missing."

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