1/17/07(MaxHealth) - Researchers at Mayo Clinic in Jacksonville,
Fla. and the National Taiwan University Hospital in Taipei, Taiwan
have discovered what to date appears to be the most common genetic
risk factor for Parkinson's disease worldwide. They believe the
majority of people carrying this genetic mutation descend from a
common ancestor about 4800 years ago. Their study was published Jan.
9 in the online edition of Parkinsonism and Related Disorders.
Researchers found that ethnic Chinese individuals carrying a
mutation they identified in the LRRK2 gene are over two times more
likely to develop the disease than non-carriers. Given the
population of China and the number of ethnic Chinese worldwide, this
mutation may predispose more people to developing Parkinson's
disease than any other genetic factor. However, researchers say not
everyone with the mutation develops the disease, and in those that
do, other genetic and environmental factors are probably in play.

Mayo Clinic neuroscientist Matthew Farrer, Ph.D., lead author on the
study, says this discovery is a small part of the ongoing genetic
revolution in medicine. "Seemingly sporadic Parkinson's disease may
be a familial disorder, and we're finding that the genetic risk
factors for Parkinson's disease are population specific," he says.

In 2004 Mayo Clinic researchers were part of a team that discovered
the LRRK2 gene and its role in Parkinson's disease. This group and
others went on to find a number of mutations in LRRK2, a gene that
codes for a poorly understood protein, leucine-rich repeat kinase 2.
One of the mutations, G2019S, has been shown to cause Parkinson's
disease in people with and without a family history of the disease.
G2019S is an especially common cause of Parkinson's disease in
Berber Arabs and Ashkenazi Jews.

However, in contrast to the G2019S mutation, which is considered a
disease causing mutation because it is rarely found in healthy,
elderly people without Parkinson's disease, the newly researched
G2385R mutation, the subject of this study, does not always lead to
disease. It is found in approximately 4 percent of the ethnic
Chinese population without Parkinson's disease, which is why
researchers consider it a risk factor rather than a causal mutation.

The G2385R mutation was first discovered in 2004 by Mayo and
Taiwanese researchers in a family of ethnic Chinese decent. One of
the study authors, Ruey-Meei Wu, M.D., Ph.D., and her group in
Taiwan, went on to find the G2385R mutation in just over 22 percent
of familial Parkinson's disease cases. "The findings that the
frequency of LRRK2 G2385R is observed at 8 percent within ethnic
Chinese patients, 4 percent in control subjects and 22 percent in
familial patients strongly suggests the G2385R variant is an
important genetic risk factor in the ethnic Chinese population," Dr.
Wu says.

Due to these findings, Wu says it will be important to look at
subtle signs of disease in asymptomatic carriers for clues about the
mutation's penetrance, meaning the extent to which symptoms
associated with disease will occur. "We can also evaluate the effect
of neuroprotection in these carriers in a long-term follow up
study," Wu says. "Epidemiology studies looking for other
environmental risk factors and their interaction with genetic risk
factors will provide clues to prevent the occurrence of this chronic
and disabling disease in the future."

Other research groups also have found the G2385R mutation is at a
higher frequency in Asian patients with Parkinson's disease, than in
matched control subjects. These types of case and control genetic
studies provide a powerful tool for researchers to find disease
genes and risk factors in homogeneous or isolated populations where
there has been little immigration.

Interestingly, the present paper's authors found evidence to suggest
G2385R carriers share a common ancestor. They performed a genetic
analysis looking at the inheritance pattern of a specific DNA
sequence along chromosome 12 that includes the LRRK2 gene.

Examining known genetic markers, which are short stretches of
repeated DNA subject to variation in the number of times they
repeat, their analysis showed a unique pattern of these DNA sequence
markers is almost always passed from generation to generation along
with the G2385R variant.

Researchers used genetic theory to estimate the level of variation
at these genetic markers between carriers and healthy non-carriers,
and used that data along with the genetic distance the markers are
away from the LRRK2 gene to estimate how many generations have been
passing on this unique stretch of DNA. Their analysis concluded that
the G2385R mutation arose approximately 4,800 years ago,
corresponding with the rise of Chinese civilization and the reign of
Yellow Emperor Huang Di, credited with inventing traditional Chinese
medicine.

This mutation does not appear to play a role in Parkinson's disease
within other racial groups. Studies to date have failed to find the
mutation in Caucasian populations. Farrer says therapeutic
interventions focused on LRRK2 will be very important to develop
given the global population affected by all the LRRK2 mutations.

Another study author, Mayo Clinic neuroscientist Owen A. Ross,
Ph.D., says although the group's findings point toward one of the
most important genetic risk factor for Parkinson's disease, he
agrees with Wu that there is still much to understand about which
carriers will develop the disease and at what age their symptoms
begin. "There are going to be other significant disease modifiers,"
he says. "The age of onset for disease is variable in G2385R
carriers and for LRRK2-parkinsonism in general. Not only may there
be environmental factors, but also other genetic factors acting on
this genomic background which determines disease presentation."

As the G2385R mutation dates so far back and is now so prevalent;
researchers have an opportunity to assess thousands of carriers and
treat them as members of one distantly related family in order to
find other genetic and environmental factors that act with G2385R to
trigger Parkinson's disease.

1/17/07(MaxHealth)