Huntington's Gene Located

After a frantic search lasting more than a decade, Harvard Medical School researchers will report this week that they have located the elusive genetic defect responsible for Huntington's disease.

The key to the defect is a short repeated sequence of DNA, just three base pairs of the millions which make up each human chromosome. With the finding, a quicker and more inexpensive test for the devastating degenerative disease of the central nervous system, and eventually a better understanding of the disease mechanism, may lead to a cure.

James F. Gusella, professor of genetics and a leading collaborator in the 10-institution search, said in a telephone interview yesterday he felt "great relief" upon discovering the defect responsible for the usually fatal disease, which killed folksinger Woody Guthrie.

"It opens possibilities for taking the defect of the disease that causes cell death and having the pathway worked out for steps to target for treatment," said Gusella, who nine years ago discovered the general location of the defective sequence.

Huntington's disease is a progressively degenerative disorder, usually striking its victims between the ages of 30 and 50. In the U.S. approximately one in 10,000 individuals, or 25,000 people, are affected, according to Philip J. Cohen, a spokesperson for the Huntington's Disease Society of America. 125,000 people are at hereditary risk for the disease.

The disease is inherited as a dominant trait, which means that children of a parent with Huntington's are at a 50 percent risk of being affected.

Gusella reports in Friday's issue of the journal Cell that he found Huntington's disease victims shared a "genetic stutter," an excessive repetition of a sequence of three nucleotide bases. The three-base segment has 11 to 34 direct copies in unaffected people, but anywhere upwards of 42 repeats in those affected.

Huntington's disease, formerly known as Huntington's chorea for the involuntary "dancelike" movements which characterize sufferers, kills brain cells and leads to a variety of both motor and mental symptoms, according to Alice R. Wexler, a supporter of the Hereditary Disease Foundation.

Patients, who become progressively weaker as the disease proceeds, often die of pneumonia or asphyxiation, and often suffer severe emotional disturbances.

There are currently drugs to alleviate the symptoms of the lethal disease, but none are available which slow the disease's progression or prevent it.

"It's a very horrible disease," said Wexler, who is the author of a forthcoming book on the search for the Huntington's gene.'

"Ultimately, victims are bedridden and fed through a straw, since they can't swallow or chew," Gusella said. "The same cell death causes intellectual loss, memory loss, and psychiatric changes like impulsive behavior and chronic depression."

Gusella and his colleagues analyzed hundreds of DNA samples from affected and non-affected individuals and families in an attempt to find the gene. Previously, he and his group had reported several "candidate defects" for Huntington's.

Gusella said the finding will improve research techniques for other hereditary diseases and may lead to a widely applicable and more accurate diagnostic test for Huntington's. Current tests require large numbers of blood samples from different family members. But the identification of the gene should make possible a single, quick and inexpensive test.

Michael R. Hayden, a professor at the University of British Columbia who is the collaboration's principal competitor in the field, said this is "a great day for families with Huntington's disease and a great step forward in this area."

Different Candidate

Hayden reports this week of a different candidate for the genetic defect, which may have a regulatory effect on Gusella's find, and emphasized that much more work still needs to be done.

"It's a terrific advance that represents the start of a new journey in trying to explore and explain how a particular gene causes disease," Hayden said. "The challenges are going to be very great, as we try to find the meaning of the discovery."

MIT Professor David E. Housman, another key collaborator with Gusella, said the next step is to figure out the underlying mechanism which causes the death of the brain cells.

According to Housman, scientists will utilize a number of strategies to determine the behavior of the gene in cells, including the possibility of using an animal model for the disease.

"This is it," said Housman, who teaches in the joint Harvard-MIT Health Sciences Training program. "The whole field will explode because of this discovery."

Cohen said he and Society chapter presidents are hopeful that the explosion of research activity will result in a cure.

"There's a lot of positive feeling," Cohen said. "I think it's tremendously hopeful in the long term.

Patients, who become progressively weaker as the disease proceeds, often die of pneumonia or asphyxiation, and often suffer severe emotional disturbances.

There are currently drugs to alleviate the symptoms of the lethal disease, but none are available which slow the disease's progression or prevent it.

"It's a very horrible disease," said Wexler, who is the author of a forthcoming book on the search for the Huntington's gene.'

"Ultimately, victims are bedridden and fed through a straw, since they can't swallow or chew," Gusella said. "The same cell death causes intellectual loss, memory loss, and psychiatric changes like impulsive behavior and chronic depression."

Gusella and his colleagues analyzed hundreds of DNA samples from affected and non-affected individuals and families in an attempt to find the gene. Previously, he and his group had reported several "candidate defects" for Huntington's.

Gusella said the finding will improve research techniques for other hereditary diseases and may lead to a widely applicable and more accurate diagnostic test for Huntington's. Current tests require large numbers of blood samples from different family members. But the identification of the gene should make possible a single, quick and inexpensive test.

Michael R. Hayden, a professor at the University of British Columbia who is the collaboration's principal competitor in the field, said this is "a great day for families with Huntington's disease and a great step forward in this area."

Different Candidate

Hayden reports this week of a different candidate for the genetic defect, which may have a regulatory effect on Gusella's find, and emphasized that much more work still needs to be done.

"It's a terrific advance that represents the start of a new journey in trying to explore and explain how a particular gene causes disease," Hayden said. "The challenges are going to be very great, as we try to find the meaning of the discovery."

MIT Professor David E. Housman, another key collaborator with Gusella, said the next step is to figure out the underlying mechanism which causes the death of the brain cells.

According to Housman, scientists will utilize a number of strategies to determine the behavior of the gene in cells, including the possibility of using an animal model for the disease.

"This is it," said Housman, who teaches in the joint Harvard-MIT Health Sciences Training program. "The whole field will explode because of this discovery."

Cohen said he and Society chapter presidents are hopeful that the explosion of research activity will result in a cure.

"There's a lot of positive feeling," Cohen said. "I think it's tremendously hopeful in the long term.