Scientists at the National Institutes of Health collaborating with researchers at the University of Medicine and Dentistry of New Jersey (UMDNJ) have localized the gene responsible for Parkinson's disease in a large family with many cases of the illness. The finding -- that the gene is located in a small region of chromosome 4 -- is seen as a major advance in understanding the biology of Parkinson's disease.
The discovery was announced today (November 14) at a news conference in Washington organized by the NIH. A scientific paper on the research is being published in the November 15 issue of the journal Science.
The collaborating scientists were from the National Center for Human Genome Research, and the National Institute for Neurological Disorders and Stroke, both at the NIH, and the Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick.
Over a period of 10 years, the researchers at UMDNJ studied a large Italian- American family that had suffered multiple cases of Parkinson's disease over several successive generations. With the help of colleagues at the University of Naples, Italy, the genealogy of the family was traced back to a common ancestor who lived in the village of Contursi in Salerno province, southern Italy, in the 18th century. Their studies of this family and other similar families established that Parkinson's could be genetically determined and defined the pattern of inheritance.
The UMDNJ researchers collected and stored DNA from members of the Contursi kindred and initiated a search for a DNA marker associated with the disease. Collaborating researchers at the NIH linked Parkinson's to a marker on the long arm of chromosome 4. A marker indicates the region of a chromosome where a disease-causing gene is located.
"The next step is to isolate the specific gene within that region and identify the mutation responsible for Parkinson's disease in this family," said Dr. Roger C. Duvoisin, William Dow Lovett professor emeritus of neurology at the UMDNJ-Robert Wood Johnson Medical School, and an author of the Science paper. "Studying a causative gene will help us discover how the disease occurs and how to develop methods of preventing or curing the disease."
Parkinson's disease, first described in 1817 by the English physician James Parkinson as the "shaking palsy," is a common chronic progressive disorder of late adult life characterized by tremors of the hands, muscular rigidity, slowness of movement and a stooped posture and shuffling gait. About 50,000 Americans are diagnosed with the disease each year; more than half a million are affected.
The research finding is the culmination of 30 years of work on the genetics of Parkinson's disease by Dr. Duvoisin and his colleagues. It also challenges the results of his own previous work. In the years 1976-1983 he led a group of researchers who examined 65 pairs of twins and a set of quadruplets in which one had Parkinson's. Since in only two of the 43 pairs of identical twins were both twins affected with Parkinson's, they concluded that heredity did not play a significant role in its cause.
But seeing an increasing number of familial cases among his patients, Dr. Duvoisin became skeptical of this conclusion. In the mid-1980s he and Dr. Lawrence I. Golbe, an associate professor of neurology at the UMDNJ-Robert Wood Johnson Medical School, began studying families with multiple cases. Two of the familial patients being treated in their New Brunswick office turned out to be distantly related cousins. As the data set grew, it developed that ancestors of both cousins had emigrated from the same small village in Italy.
Dr. Golbe then sought the assistance of Dr. Giuseppe Di Iorio of the University of Naples medical faculty in tracing the family's origins in Italy. Together they identified Italian branches of the family and were able to define a pedigree, or family tree, extending over 11 generations and comprising more than 400 individuals. They confirmed the presence of Parkinson's in 60 family members. This is the largest known multicase Parkinson family in the world.
In 1990, Dr. Duvoisin was named William Dow Lovett Professor of Neurology, an endowed chair that came with a $3.5 million gift from a grateful patient suffering from olivopontocerebellar atrophy (OPCA), a Parkinson-like condition. The gift established the Lovett Laboratory of Molecular Neurogenetics. He recruited Dr. Alice Lazzarini as director of clinical genetics and Dr. William G. Johnson to direct the Lovett Laboratory and head a new division of neurogenetics.
Dr. Johnson had been studying the genetics of Parkinson's disease for more than 10 years at Columbia University College of Physicians and Surgeons. He had collected over 200 families with multiple cases of Parkinson's and had been collaborating with Drs. Golbe and Duvoisin collecting and analyzing DNA from the large Contursi kindred. When Dr. Johnson joined Dr. Duvoisin's department, he brought with him a DNA bank containing specimens from cases of familial parkinsonism.
With other members of the team, Dr. Lazzarini did a study of familial aggregation in patients attending Dr. Duvoisin's clinic and found that familial Parkinson's was relatively common. She defined the pattern of inheritance in 80 multicase families.
Drs. Golbe, Lazzarini and other colleagues traveled throughout the United States and Italy to examine Contursi family members and collect blood samples. In the Lovett Laboratory, Dr. Johnson's staff extracted DNA from the blood samples and began a search for a linked DNA marker.
In August 1995 Dr. Duvoisin presented the available evidence for a genetic cause of Parkinson's disease at a research workshop in Washington sponsored by the NIH. Dr. Robert Nussbaum, chief of the Laboratory of Genetic Disease at the National Center for Human Genome Research, and Dr. Zach Hall, director of the National Institute for Neurological Disorders and Stroke, impressed with the work done on the Contursi pedigree and Dr. Lazzarini's genetic analysis of Parkinson's, proposed a collaboration to accelerate the search for a Parkinson's gene.
A year later the gene marker on chromosome 4 was found by Dr. Nussbaum's associates Dr. Mihael Polymeropoulos and Dr. Joseph Higgins in the DNA samples provided by Dr. Johnson.
The UMDNJ-Robert Wood Johnson Medical School is one of three medical schools of the University of Medicine and Dentistry of New Jersey. UMDNJ comprises New Jersey's only medical schools, the state's only dental school, a nursing school, a graduate school of biomedical sciences and a school of health related professions on campuses in Newark, Piscataway/New Brunswick, Camden and Stratford. UMDNJ also operates University Hospital, Newark, and University Behavioral HealthCare. It is affiliated with more than 100 health care and educational institutions throughout the state.