VANCOUVER, British Columbia — The gene responsible for oculopharyngeal muscular dystrophy (OPMD), a late-onset disease that begins most commonly after the age of 50, has been discovered by an international team of scientists led by Guy Rouleau, at Montreal General Hospital and the Centre for Research in Neurosciences at McGill University.

In the February issue of Nature Genetics, the team not only reported the discovery of the gene, but defined a previously unknown mutation responsible for this slowly progressive autosomal dominant disease.

As its name suggests, patients afflicted with OPMD have dystrophy of the eye and throat muscles, causing drooping of the eyelids and swallowing problems. Both these difficulties may slowly progress until the eyelids nearly or completely cover the eyeball and the ability to swallow is lost.

To correct the involuntarily closed eyelids, patients receive surgery. For swallowing problems, a feeding tube is placed into the stomach, thereby completely bypassing the pharynx.

In addition to droopy eyelids, the muscles that control eye movements may also be affected. The degree of involvement may range from mild restriction of eye movement in a single direction to severe restriction, in which eye movement in any direction is virtually nonexistent.

OPMD has a high incidence of carriers in the French Canadian population, where one in 1,000 is found in the province of Quebec. In fact, it is said that all cases of OPMD in that population can be traced to a single ancestor. In 1995, Rouleau, a member of the Canadian Genetic Diseases Network (CGDN), in Vancouver, and his colleagues linked OPMD to a region on the long arm of chromosome 14 (14q11.2-q13).

In this most recent paper the researchers report the isolation of poly(A) binding protein 2 gene from a 217-kilobase candidate interval on chromosome 14. A GCG repeat encoding a polyalanine tract located at the N terminus of the protein was found to be expanded in 144 OPMD families that were screened.

Rouleau said this discovery is crucial because it is believed that almost 100 percent of the carriers of the gene will eventually develop the disease and pass the condition on to half of their children because of its autosomal dominance characteristics.

A simple diagnostic blood test should be available within a relatively short period, allowing presymptomatic diagnosis, Rouleau indicated.

Insights Into Huntington's Discovered

In the same issue of Nature Genetics, CGDN scientific director Michael Hayden reported on new research findings that may assist in reducing human susceptibility to Huntington's disease (HD).

HD is associated with a gradual deterioration of brain cells that leads to the onset of disease symptoms by the age of 40. The sequence of events that follows results in severe physical and behavioral deterioration and ultimately death.

Hayden and his colleagues provided evidence that a process of polyglutamine expansion in the protein production of the mutated HD gene leads to the formation of large intracellular aggregates.

These "Huntington-containing" aggregates disrupt normal cellular architecture and increase the incidence of cell death. Further, there appears to be a connection between the number of cells with clumps and the degree of apoptosis.

The length of the protein itself influences the site in the cell where clumping occurs, and the shorter the protein, the worse the effect. The researchers said these findings provide new therapeutic directions for HD that include preventing shortening of the protein.

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