Gene Causing Huntington’s Disease Found
After the longest and most frustrating search in the annals of molecular biology, an international team of researchers has located the defective gene that causes Huntington’s disease, a crippling disorder that afflicts about 30,000 Americans.
The discovery will immediately make possible cheaper and more accurate tests to identify people who will develop Huntington’s. Researchers said that the unusual nature of the genetic defect will allow them to predict the age at which the disease will strike.
The discovery of the gene, whose function is still unknown, may also lead to the first treatment for the disorder, which is characterized by progressive physical and mental deterioration. An estimated 150,000 Americans are at risk of developing the disorder because of their genetic origins.
The discovery, reported today in the journal Cell, “may prove to be the crown jewel of recent neurogenetic discoveries,” said Dr. Murray Goldstein, director of the National Institute of Neurological Disorders and Stroke.
“This is a big fish that finally got caught after many close scrapes,” said molecular geneticist Francis Collins of the University of Michigan, a member of the research team who has been nominated to be head of the National Center for Human Genome Research. “This time it didn’t get away.”
“I’m just ecstatic,” added Nancy Wexler, president of the Los Angeles-based Hereditary Disease Foundation, which helped fund and coordinate the search for the gene. “This is a quantum leap, not something that is just a little incremental step.”
Isolation of the Huntington’s gene was the second major genetic discovery this month, a sign of the fast pace of genetic research stimulated by new molecular biology techniques. Three weeks ago, researchers announced the discovery of the gene for amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.
Physicians are already planning clinical trials of the first therapies based on that gene discovery, and Wexler and others hope similar progress will accompany today’s announcement.
Huntington’s disease most often strikes people in their mid-30s, but the age of onset varies from under 20 to more than 60. It inevitably kills its victims, among the most famous of which was folk singer Woody Guthrie.
The disease attacks both body and mind by killing brain cells. It begins with small involuntary movements that gradually overwhelm all parts of the body. It also interferes with thought processes, leading to dementia and other mental disturbances, particularly depression.
Children of a victim have a 50% chance of developing the disorder. Geneticists can now detect whether those offspring will get the disorder with 95% accuracy, but the tests are expensive and require blood samples from many members of the family to perform what are known as linkage tests.
With the discovery of the new gene, Wexler said, “People who couldn’t use linkage tests can now walk in the door and find out whether they have it.”
The search for the Huntington’s gene has been intense since 1983, when researchers reported that the gene was located somewhere on chromosome 4, one of the 23 sets of chromosomes that make up the human genetic blueprint. But the research bogged down because the area of the chromosome targeted for the search contains an unusually dense concentration of genes--more than 100, compared to the three to four that might normally be found in another chromosome section of similar length, Collins said.
Isolating the right gene took the combined efforts of nearly 60 people at six institutions. Research was conducted at Massachusetts General Hospital, UC Irvine, the Massachusetts Institute of Technology and the University of Michigan, the Imperial Cancer Research Fund in England and the University of Wales. They published the paper jointly under the name of the Huntington’s Disease Collaborative Research Group.
Usually, when a new gene is found to be linked with a disease, researchers can compare the gene’s composition to others for clues about its role in the disorder. But the Huntington’s gene is unlike any previously seen, Collins said, and researchers are trying feverishly to figure out what it does.
The Huntington’s gene shares a similarity with the genes for three other inherited disorders that have been identified in the past year--fragile-X syndrome, myotonic dystrophy and spino-bulbar muscular atrophy. In each case, a short segment of the affected gene is repeated a number of times--the molecular equivalent of a stutter, said molecular biologist James Gusella of Massachusetts General Hospital.
Preliminary results indicate that the number of times the gene segment is repeated correlates with the age of onset of the disease. That is, if there are 100 or more repeats, the disease begins very early in life, while if there are 35 or fewer it begins after the age of 60. If this correlation can be confirmed, then geneticists could count the number of repeats in a potential Huntington’s patient and predict the age of onset.
But Wexler cautioned that “we need to have more research to know whether we have that correlation.” It would be “unethical” to predict the age of onset without further research, she said.