Scientists Find a Gene that Grows Longer with TimeBy Karen Kaplan
A gene recently implicated in the most common form of muscular dystrophy can increase in length from generation to generation, scientists at the Center for Cancer Research report in today's issue of the journal Cell. The longer form of the gene can produce symptoms ranging from cataracts to mental retardation, and even sudden death.
The finding comes just two weeks after the same researchers discovered that the gene, which works by an unusual duplication mechanism, is linked to myotonic dystrophy (DM), the most common form of muscular dystrophy (MD).
This latest discovery may lead to earlier and more accurate detection of myotonic dystrophy, as well as development of strategies for a cure and for studying other genetic diseases.
"All of us have begged for a breakthrough and now we have it," said Richard T. Moxley III, a neurologist and pediatrician from the University of Rochester who has been treating and studying myotonic dystrophy for nearly 20 years. "I think there's tremendous hope for patients."
The work, which also involved research teams from England and Wales, indicates that when a gene on chromosome 19 contains a trinucleotide sequence 50 times or more, symptoms of MD can occur in patients. Further, the DNA sequence may duplicate or triplicate itself as the gene is passed from one generation to another, resulting in more serious illness, including congenital myotonic dystrophy.
In today's article, researchers in Professor of Biology David A. Housman's laboratory led by David Brook, a postdoctoral fellow at the CCR, describe how a chemical sequence, the trinucleotide repeat consisting of the bases cytosine, thymine, and guanine (CTG), repeats from 50 to 2000 times or more in patients with myotonic dystrophy. The number of repeats is closely correlated with the severity of DM symptoms.
"It's a triplet repeat and we know that it resides in a protein kinase," said Brook, who has studied myotonic dystrophy for nine and a half years. Protein kinases, enzymes which modify other proteins, are important for many different body tissues, and an abnormality in one of them could affect several organs.
"Protein kinases are understood, so it will be easier to work out a potential treatment" for myotonic dystrophy, he continued.
The discovery was made by closely analyzing a region of chromosome 19 which was believed to contain the amplified CTG fragments in DM patients. Researchers sequenced these samples and found that healthy people had between five and 27 copies of the triplet repeat. Then they compared the sequences in healthy patients with those in mildly affected myotonic dystrophy patients and found that the sequences in myotonics were at least twice as long as in normal people.
In healthy people, the CTG sequence usually occurs between five and fifteen times, although finding up to 27 repeats is not uncommon. Myotonic dystrophy patients with 50 CTG repeats may appear normal or display minor symptoms, such as cataracts, drooping eyelids or trouble releasing a grip.
Researchers suspect that patients with more symptoms, including muscle wasting, have 300 CTG repeats in the critical gene, and that those who suffer from congenital myotonic dystrophy have up to 2000 or more CTG repeats. Congenital DM is usually present in infancy and results in severe mental retardation.
"There's a distinct gap between 27 and 50 repeats, so there must be a duplication" of the sequence in order to get the disease, Brook said. "We don't know what mechanism underlies this amplification," he continued, indicating that this is a subject for future research.
Four other research teams which have studied myotonic dystrophy will corroborate these results in the March 6 issue of the journal Science.
Myotonic dystrophy, which usually appears in adolescence or early adulthood, results in weakness and wasting in some muscles and often produces difficulty in muscle relaxation, a condition called myotonia. The disorder also causes other effects, including heart problems, gastrointestinal complications, cataracts, premature balding, mental slowness, and sleep disorders, according to the Muscular Dystrophy Association, a sponsor of the research.
Genes have novel mechanism
Earlier this month, researchers in Housman's laboratory reported that the gene that causes myotonic dystrophy can lengthen from one generation to the next, so that mildly affected parents could pass on a more severe form of the disease to their children. It is now clear that lengthening can occur when the CTG series duplicates itself as the gene is passed on. As a result, the onset of symptoms can occur earlier in each generation in what is called "anticipation," although the sequence is not duplicated in every generation.
"Our first hint that the gene might be working this way came last year when Fragile-X mental retardation syndrome was cloned and found to have a triplet repeat," Brook said. "Fragile-X is similar to myotonic dystrophy in that the syndrome gets worse in succeeding generations, so it was suggested that there might be a repeat in myotonic dystrophy too."
Myotonic dystrophy is the third disease found to be related to a gene segment which can change as it is passed from one generation to the next. In addition to Fragile-X syndrome, this mechanism operates in spinal and bulbar muscular atrophy, a wasting disease. "This opens up some new thinking about genetic regulation," Moxley said.
Implications of research
Although one in every 7000 to 8000 people worldwide is afflicted with myotonic dystrophy, Brook suspects that many more people may be carriers of the DM gene and therefore "at risk" of developing DM symptoms.
"There are probably many people with very few symptoms that appear normal and are minimally affected and never go to a doctor," Brook explained. "They may have cataracts, which is a common symptom of people who are mildly affected, or they have problems releasing a grip, but it's not that bad and they don't worry about it. These people may pass the (defective) gene on to their children and grandchildren" who may develop a far more severe case of myotonic dystrophy, he said. Children of myotonics have a 50 percent chance of inheriting a faulty gene.
Now that the gene's reproduction mechanism is better understood, "people have started to think that it's likely that other diseases operate on this level," Brook said. Diseases which worsen in successive generations and which display a variance in the age of onset have been targeted. Currently, researchers are focusing their attention on Huntington's Disease, a hereditary brain disorder.
Another outcome of this recent discovery is that early detection tests for myotonic dystrophy, including tests before birth, will improve now that researchers know exactly where to look for the faulty gene. "If you're worried that you might have a severely affected infant," Moxley said, new tests will make it easier to determine the severity of the condition by isolating the gene and counting the number of CTG triplets.
"This is pertinent to patients right now," said Moxley, who lost a brother to myotonic dystrophy last year. "We can identify affected individuals without screening their whole families."
Also, since the gene resides in a familiar protein kinase, researchers should be able to understand the disease more easily.
Brook said he suspects that most myotonics "are the result of a common ancestral event" which must have occurred very early in evolution, since the disease has been found in North America, Europe, China, and Japan. He predicted that myotonic dystrophy must exist in Asia and in Africa, but that "there are so many health problems there that the disease would rarely show up as such."
As in all genetics research, these findings raise complicated and troubling ethical questions. For example, "now that it's likely that more people are carriers [of myotonic dystrophy] than were originally thought, how do we identify people who are potentially at risk? Should we?" Brook explained.
"The ethical question is slightly different for this disease because the disease can be passed on with increased severity," Brook continued. "It's a novel mechanism, and it has an additional ethical dimension."