The Genetics of Parkinson's Disease

The Search for a Gene
Gene Discovery
Genetic Risk


The Search for a Gene




When scientists set out to look for a gene that causes a particular disease, they need some sort of guide.  The search for a gene can be compared to:  "trying
to find a street on a city map that lists the city's major landmarks, but not the streets."  The maps available today are still somewhat incomplete.  Thus, looking for a gene is a long and difficult task.  There are several factors that can slow down genetic analysis.  Incomplete penetrance, the failure of a genetic disease to show overt symptoms in persons who have the underlying genetic defect can make tracing the gene for Parkinson's difficult. The fact that Parkinson's often appears late in life causes more problem since people may die of other causes before their Parkinson's symptoms surface.  Another obstacle is the presence of more than one gene that can independently cause a disease. If families carrying different Parkinson causing genes are analyzed, it can be difficult to identify the relationship between a specific gene and the disease.  To date, there are several pedigrees for familial Parkinson's disease that are now large enough to support an all out gene search, eliminating complications such as the presence of different disease-related genes in different families.


Gene Discovery


In 1996, M. Polymeropoulos, MD, and his colleagues at the National Institutes of Health (1996) reported finding a gene associated with PD on the long arm of chromosome 4. The researchers analyzed DNA from a single, large Italian family with many individuals showing signs of a rare, early onset form of PD. Since the discovery, Dr. Polymeropoulos and his group have reported further findings regarding the chromosome 4-linked gene.  In 1995, a gene known as alpha-synuclein was mapped to the long arm of chromosome 4 by other researchers.  Dr. Polymeropoulos has identified a mutation within the synuclein gene in the individuals with PD not only in the large Italian family, but also in three Greek families who have shown an early age of onset and autosomal dominant inheritance. Furthermore, a large number of control samples (individuals without PD) were studied and none of them carried the mutation. This is very strong evidence to support the idea that this mutation as the gene for early onset, autosomal dominantly inherited PD.  This means that the gene linked to the disease is not on the 23rd chromosomal pair responsible for determining the sex of the individual.  Rather, the gene is located on one of the 22 remaining chromosomal pairs, specifically chromosome number 4.  Because the Parkinson's gene is not located on the sex gene but rather one of the 22 remaining autosomes, it is referred to as an autosomal disorder (Duvoisin).  The gene for Parkinson's disease appears to be transferred in a dominant fashion rather than recessively as in cystic fibrosis.  This means that only a single copy of the gene is needed to cause the disease.  In recessive genetic disorders, a copy of the disease gene  must be inherited from both parents.  This means genetic transfer of the Parkinson's gene is more common than it would be if it were merely a recessive trait.  More work is needed to specifically define this geneís location and the abnormal protein that is produced. While this finding may have no direct bearing on random cases of PD and non-autosomal dominant familial PD, it does provide an important piece of the road map in understanding the genetics of PD.  The gene(s) which are responsible for familial PD are known as susceptibility genes. Having one or more of these susceptibility genes, in combination with yet unknown environmental factors, may significantly increase an individualís chance of developing PD.
 


Finding a Gene for Parkinson's Disease


 



Genetic Risk
     The good news for children of Parkinson's disease patients is that penetrance is often not completed within a normal life span.  Because the Parkinson's gene is transferred in a dominant fashion, each offspring has a 50% chance of carrying the disease gene.  However, very few people who carry the gene will show Parkinsonian symptoms within their lifetime.  The actual risk for children of Parkinsonian patients developing symptoms within their lifetime, is estimated to be between 10 and 15% (Tanner, 1999).


 

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