In a discovery that could have implications in combatting a number of serious diseases, researchers have found the gene that causes myotonic dystrophy, a wasting disorder that is the most common form of muscular dystrophy in adults.
Only two weeks ago, scientists announced that they had narrowed the search to a very small region of the human genetic blueprint. Now, in papers scheduled to be published today in the journal Cell and on March 6 in Science, three groups of researchers announce that they have identified the defective gene and are studying its function in the cell.
The researchers are already using the discovery to perform prenatal screening for myotonic dystrophy, which affects one in every 7,000 to 8,000 people worldwide. Understanding how the key protein functions could open the door to development of the first therapy for the disorder.
Prenatal screening is particularly important for myotonic dystrophy because the mutations become more extensive as the gene is passed from parent to child and the disease becomes more severe with each passing generation.
The discovery "will not only improve treatment in myotonic dystrophy, but may jolly well increase our ability to understand other illnesses and their genetic mechanisms," said neurologist Richard Moxley III of the University of Rochester School of Medicine. Those diseases may include mental retardation, diabetes, obesity and even cancer.
But molecular biologist J. David Brook of the Massachusetts Institute of Technology, leader of one of the groups, cautioned that years will be required for the development of new drugs. "Treatment is not just around the corner," he said in a telephone interview.
Myotonic dystrophy, also known as Steinert's disease, is different from the better-known Duchenne muscular dystrophy. The latter disorder strikes one in every 3,500 males early in life, confining them to wheelchairs by age 12 and causing death in many cases in their 20s. The gene that causes it was discovered in 1987, and researchers are testing new therapies based on that discovery.
In contrast, myotonic dystrophy affects both men and women and has a broad range of symptoms. The mildest form typically develops in middle or old age and may have no symptoms other than cataracts. The classical form develops early in adult life and is characterized by myotonia (an inability to relax muscles), muscle weakening, heart problems, premature balding, mental slowness and sleep disorders. Victims are typically confined to wheelchairs and die in their 50s and 60s.
The most severe form of myotonic dystrophy is congenital and often is immediately fatal.
The new research explains this variability in symptoms for the first time. The defect, the teams said Thursday, involves the repetition of a small chemical segment called CTG in the gene for a protein called myotonin protein kinase.
In a healthy individual, the CTG segment is repeated from five to 27 times. For unknown reasons, the number of repeats sometimes increases when the gene is passed on to children. The more times the segment is repeated, the more severe the symptoms of the disease.
If the number of CTGs reaches 50, Brook said, the first symptoms appear in old age. If the number is 200 to 300, the classical form of the disease develops. If 2,000 copies appear, the disorder may appear in the teen years. And with more copies, symptoms are present at birth.
Myotonic dystrophy is the third genetic disorder in which this progressive phenomenon, called "genetic anticipation," is observed. The other two are fragile X syndrome, the most common form of mental retardation, and spinal and bulbar atrophy, a rare wasting disease. The genes for both of these were discovered earlier this year. Dissecting the mechanism by which myotonic dystrophy occurs should shed light on those diseases as well, said Moxley, who was not on the teams that discovered the new gene.
The myotonic dystrophy gene has another unusual characteristic as well. The observed defect is not in the part of the gene that would actually form a protein with abnormal function, but rather in a portion that would trigger production of abnormally large or abnormally small amounts of the protein.
Such a scenario leads to optimism that a treatment can be found. Theoretically, the researchers said, it should be easier to find drugs that would stimulate or block production of the protein than to find drugs that would mimic the protein's activity.
But the researchers do not know the function of myotonin protein kinase or even where it is located in the cell, so they have no idea whether there is too much or too little of it. They are working to find that out.
Information about the gene and the biochemical mechanism of the disorder could affect a number of other diseases, Moxley said. One characteristic of myotonic dystrophy victims, he noted, is increased insulin resistance. Insulin resistance is also found in some types of diabetes, in obesity and even in aging. Understanding how the kinase defect causes it in myotonic dystrophy may thus lead to better understanding of those other conditions.
Finally, the activity of protein kinases have been widely implicated in cancer. According to one of Brook's co-authors, medical geneticist Duncan J. Shaw of the University of Wales in Cardiff, the discovery could yield insights there as well.
The leaders of the other teams announcing the gene discovery are geneticist C. Thomas Caskey of the Baylor College of Medicine in Houston, geneticist Robert G. Korneluk of the Children's Hospital of Eastern Ontario in Ottawa, geneticist Pieter de Jong of the Lawrence Livermore National Laboratory and geneticist Be Wieringa of the University of Nijmegen in the Netherlands.
Defective Gene Researchers have found the defective gene that causes the most common form of muscular dystrophy in adults. It is located at one of of chromosome 19, one of the 46- chromosomes that contain the genetic blueprint of a human. Chroomsome 19 In the healthy form of the gene, one small segment called CTG is repeated five to 27 times (symbolized by the smaller 5-segment bar above). In the defective form, the CTG segment is repeated 50 to several thousand times (shown by the long bar).