Different mutations in single gene suggest Parkinson's is primarily an inherited genetic disorder

JACKSONVILLE, Fla. – Two new international studies by researchers at the Mayo Clinic site in Florida are rounding out the notion that Parkinson’s disease is largely caused by inherited genetic mutations that pass through scores of related generations over hundreds, if not thousands of years. These genetic influences, which can be small but additive, or large and causative, overturn common beliefs that the neurodegenerative disease mostly occurs in a random fashion or is due to undetermined environmental factors.

These latest studies bring the total of number of disease-related mutations in an as yet poorly understood gene, leucine-rich repeat kinase 2 (LRRK2), to seven, all of which are linked, either weakly or strongly, to typical, late onset development of Parkinson’s disease in people around the world. One mutation (R1628P) doubles the risk of Parkinson’s disease in ethnic Chinese, according to a study published on Wednesday, April 16, 2008 in the online edition of the Annals of Neurology. The second study, published April 15 in Neurology, demonstrates that another very rare mutation (R1441C), found in people on three continents, increases risk by more than 10-fold.

The R1628P was identified by the strong collaborative effort of researchers from Taiwan, Singapore, Japan, and the U.S. The research institutions included the National Taiwan University Hospital, led by Dr. Ruey-Meei Wu, Chang Gung Memorial Hospital led by Dr. Yih-Ru Wu, National Neuroscience Institute of Singapore led by Dr. Eng-King Tan and Juntendo University, led by Dr. Nobutaka Hattori. This group believes the R1628P mutation arose from a single individual in the Han Chinese population about 2,500 years ago and has since spread through generations of descendants, wherever they live. This is the second common LRRK2 mutation discovered in Asians –a mutation labeled G2385R believed to have originated 4,500 years ago was first reported in the journal ‘Neurogenetics’ in 2006 and subsequently confirmed by several groups. Lrrk2 G2385R and R1628P predispose over 100 million Chinese people to Parkinson’s disease.

“The picture that is emerging of Parkinson’s disease is one in which genetic risk factors, passed down through the population for hundreds or thousands of years, add up to substantial susceptibility within a single individual, and, with some possible environmental influences, can result in disease,” says Mayo Clinic neuroscientist Owen A. Ross, Ph.D., first author on the Annals of Neurology study.

“These types of mutations are important because the goal of this research is to be able to screen people who are most at risk because of their genetic profiles, and design therapies that interfere with the disease process,” Dr. Ross says.