Huntington Disease

In 1972, Wexler learned of several large, interrelated families affected with Huntington disease who lived in small villages along Lake Maracaibo in Venezuela. Wexler realized that this was a unique and valuable resource due to the large family pedigree. The larger the family tree, the easier it is to find genes by linking their location on the chromosome to specific DNA markers within the genome. In 1979, she began making annual trips to Lake Maracaibo. With the help of a team of investigators, she created a genealogy of the families and, beginning in 1981, took blood samples from both sick and the healthy family members. Wexler was convinced that the key to Huntington disease lay locked in the DNA of these families.

In 1983, James Gusella, a young scientist at Massachusetts General Hospital, began applying a new technique of molecular biology to the blood samples from Venezuela. He was looking for patterns that were present in the DNA sequences of people with Huntington disease but absent in the DNA of people without the disease. If one particular pattern of DNA was always associated with the illness in a given family, then it could be used as a marker for the disease gene. For instance, if it were true that people who developed the disease always had green eyes, then scientists could say that the gene that is responsible for green eyes located in a position along the DNA strand that is close to the gene that causes the disease. This genetic evaluation is called linkage analysis.

Eventually, Gusella found a genetic marker for Huntington disease, and remarkably it was almost immediate. Although the gene itself was still unknown, the discovery of this genetic marker made it possible to create a genetic test for the disease (linkage analysis), in the following year. By studying blood samples from several family members, persons who had a parent die of Huntington disease could be told whether or not they had inherited the genetic marker linked to the disease in their family. Other scientific teams also began using linkage analysis to search for disease genes as a result of these studies.

Even though the discovery of the marker indicated to scientists the general location of the gene itself, that gene hunt proceeded slowly. At Wexler's urging, and in a break from usual scientific practice, a consortium of six scientific teams worked together to find the gene. Finally, on March 26, 1993, in the scientific journal Cell, the 58 members of the Huntington's Collaborative Research Group announced to the world the discovery of the gene that causes Huntington disease.