Single Copy Of Parkinson's-risk Gene Mutation May Lead To Earlier Symptom Onset

"This study reinforces the fact that there are multiple mechanisms behind Parkinson disease and will lead us to examine other pathways with which parkin interacts," says James Gusella, PhD, director of the MGH Center for Human Genetic Research, the study's senior author. The report is part of the larger GenePD project, an international collaborative study of siblings with Parkinson disease, which is based at Boston University Medical Center and led by Richard Myers, PhD.

Parkinson disease is a neurodegenerative disorder characterized by tremors, rigidity, difficulty walking and other symptoms. It is caused by the destruction of brain cells that produce the neurotransmitter dopamine and is the second most common neurodegenerative disorder. The condition's prevalence increases with age – appearing in 1 percent of those over 60 and 4 to 5 percent of those over 85 – but it can develop in much younger patients. While the cause of most cases of Parkinson's is unknown, there are rare, inherited forms. Five genes have been identified as increasing the risk for Parkinson's – parkin mutations inherited from both parents being the most common genetic cause of early-onset disease – but additional susceptibility genes are yet to be found.

Since finding new genes is a goal of the GenePD study, a preliminary step is to identify those whose familial Parkinson's can be attributed to one of the known genes. Focusing on parkin, the researchers began by analyzing samples from 329 families with at least two affected members, collected from 20 sites in North America, Europe and Australia. From this collection, samples from two groups of families were selected: those in which affected siblings have inherited identical versions of the chromosome 6 region in which parkin resides and those in which at least one affected member developed symptoms before age 54, since early-onset Parkinson's involves symptoms appearing before the age of 50.

For each of the 183 families selected, complete genetic screens were done on the patient with the earliest onset of symptoms. If that patient was found to have parkin mutations, genetic screens were completed on other affected family members. Parkin mutations were found in 23 (12.6 percent) of the 183 screened families. Among the families with parkin mutations, 13 had at least one member with mutations on both copies of the gene, while in 10 families affected members had a single mutated copy of parkin. Eighteen different parkin mutations were identified, four of which had not previously been described.

The average age of onset in all those with parkin mutations was about 43. But among the families in which the parkin chromosome markers were identical, those with no mutations in the gene developed symptoms at an average age of about 61, those with a single abnormal copy of parkin at around age 50, and those who inherited two mutated copies had onset at around age 36.

"This is the first time anyone has shown that a single parkin mutation can lower the age of onset," Gusella says. "We don't know if that would be sufficient to cause the disease. It's more likely that these mutations increase susceptibility to other factors underlying the development of Parkinson's. The result also lets us know that future researchers shouldn't just study the effects of completely knocking out the parkin gene, we'll need to examine knocking out a single copy as well," he adds. Gusella is the Bullard Professor of Neurogenetics at Harvard Medical School.

Co-authors of the report at MGH are first author Mei Sun, MD, PhD; John Growdon, MD; Tammy Gillis, and Marcy MacDonald, PhD. Along with Myers, co-authors at Boston University School of Medicine are Jeanne Latourelle; Ranjana Prakash; Sally Williamson; Gang Xu, PhD; Jemma Wilk, DSc; Marie Saint-Hilaire, MD; and Anita DeStefano, PhD. The study was supported by grants from the Bumpus Foundation and the U.S. Public Health Service.

Additional co-authors are Frederick Wooten, MD, University of Virginia; Mark Lew, MD, University of Southern California; Christine Klein, MD, University of Lubeck, Germany; Lawrence Golbe, MD, and Margery Mark, MD, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School; Brad Racette, MD, and Joel Perlmutter, MD, Washington University School of Medicine, St. Louis; Garth Nicholson, PhD, University of Sydney, Australia; Carlos Singer, MD, University of Miami, Florida; Ray Watts, MD, University of Alabama at Birmingham; Peter Pramstaller, MD, General Regional Hospital, Bolzano, Italy; Scott Sherman, MD, University of Arizona; Irene Litvan, MD, University of Louisville School of Medicine; Holly Shill, Barrow Neurological Institute, Phoenix, Arizona; Abbas Parsian, PhD, University of Arkansas for Medical Sciences; Mark Guttman, MD, University of Toronto; Oksana Suchowersky, MD, and Nancy Labelle, BN, University of Calgary; Sefano Goldwurm, MD, PhD, and Gianni Pezzoli, MD, Instituti Clinici de Perfezionamento, Milan; Kenneth Baker, PhD, Cleveland Clinic Foundation; David Burn, MD, and Patrick Chinnery, MD, Newcastle General Hospital, England; and Peter Vierette, MD, Klinikum Lippe-Lemgo, Lemgo, Germany.