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The Gene Hunter

The scientist who discovered the gene responsible for causing Huntington’s disease continues his pursuit for other gene targets.

By Lauren Ware // The MGH Research Issue 2011
Jim Gusella

Denise Bosco for Proto

James Gusella, director of the Center for Human Genetic Research at MGH, identified the gene responsible for causing Huntington’s disease, working with the lab of MGH researcher Marcy MacDonald. Gusella’s lab has participated in the initial gene mapping or cloning for many other inherited disorders as well, and it is currently using the knowledge of the Huntington’s disease gene to investigate the disease’s biological mechanisms.

Q: What led you to study Huntington’s disease?

A: As a student, I had just developed a technique for cloning DNA based on where it’s located in human chromosomes, instead of by what protein it made. The next step was to find the location of a gene interesting enough to clone. Joe Martin, who had just become head of the neurology department at MGH, was interested in Huntington’s. No one knew where the Huntington’s disease gene was, only that it was inherited in a dominant fashion—it took just one copy of the gene to give someone the disease. It continued to be passed on because most people never showed symptoms until after they’d had children.

Q: It’s said that your discovery spurred the Human Genome Project.

A: It really got people thinking about using genetic tools for understanding, diagnosing and, ultimately, treating disease. The Huntington’s disease work was the first mapping of a gene that no one had known the location of, using only DNA markers. As a result, scientists started talking about a human genome project, because we realized we could map other disease genes using the same strategy.

Q: After finding the gene, what challenges remain?

A: We still don’t fully understand the function of the Huntington’s protein. We had learned that the mutation was a gene sequence in which CAG, representing the chemical bases cytosine, adenine and guanine, was repeated over and over, more than 34 times. We do know that the CAG repeat codes for the amino acid glutamine, so people with Huntington’s disease have extra-long tracts of glutamine in their Huntington’s protein. It turns out that the longer the repeat, the earlier the onset of the disease, on average. We also learned that if we knock out the function of the Huntington’s protein in a mouse, the mouse can’t live, so Huntington’s disease doesn’t involve a complete loss of function of the protein.

Q: What’s the focus of your current work on Huntington’s?

A: Studies suggest that several other genes affect Huntington’s disease, and we’re trying to identify some of those. If we can locate them, they’ll be targets for therapeutics.


Video: The Gene Hunter

Jim Gusella

James Gusella discusses the future of genetics research.

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