Researchers Report Huntington's Finding

Gene Reveals Possible Defective Protein

A group of Harvard Medical School researchers is getting closer each month to discovering the genetic defect responsible for Huntington's disease.

In a paper appearing today in an Oxford University journal, Assistant Professor of Neurology Marcy E. MacDonald and Professor of Genetics James F. Gusella reported that a DNA sequence within the general location of the Huntington's defect encodes an enzyme similar in structure to those involved in brain cell communication.

The finding, published in today's issue of Human Molecular Genetics, is significant because Huntington's--the disorder which felled folksinger Woody Guthrie--is thought to be caused by a biochemical abnormality in the brain.

More than 20,000 U.S. residents suffer from Huntington's, a fatal disease, which usually manifests during middle age. Symptoms include progressive loss of muscle control and cognitive function, often leading to dementia.

In 1983, Gusella discovered the general location of the defective DNA sequence on chromosome four. He has since attempted to identify all of a possible 100 proteins encoded on the chromosome.


The enzyme reported today has a makeup which places it as a new member of a family of enzymes known as G protein-coupled receptor kinases, according to the report's au- thors. These kinases are responsible forturning off signal transduction, the cascade ofreactions involved in communication with othercells.

"We suggest that the protein may also functionin a similar way to G protein-coupled receptorkinases," MacDonald said yesterday. "We do nothave evidence that this gene is defective inHuntington's disease patients."

The paper's authors suggest that a kinase genedefect might cause constant activation of signaltransduction receptors and may result in the slowof death of neurons often seen in Huntington'spatients.

But they caution that further examination ofcandidate genes and actual defects is necessarybefore concluding that a given defective gene isresponsible for the disease.

"It's like being a presidential candidate,"MacDonald said. "It doesn't mean you'renecessarily going to be president."

MacDonald and Gusella, both members of theMolecular Neurogenetics Unit at the Mass. GeneralHospital Neuroscience Center, reported thediscovery early last month of another candidategene encoding alphadducin, a protein present inhigh concentrations in the brain.

That report followed an April paper in whichGusella, director of the unit, further localizedthe defective gene to a short segment ofapproximately 500,000 base pairs shared by 30 to40 percent of DNA collected from Huntington'spatients and their families

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