Parkinson's Genes: One In, One Out
Parkinson’s Genes: One In, One Out
ABSTRACTS & COMMENTARY
Sources: Polymeropoulos MH, et al. Mutation in the a-synuclein gene identified in Families with Parkinson’s disease. Science 1997;276:2045-2047; Wilhelmsen K, et al. Is there a genetic susceptibility locus for Parkinson’s disease on chromosome 22q13? Ann Neurol 1997;41:813- 817.
An international research collaboration has led to the identification of a gene mutation on chromosome 4 that is responsible for an early onset, hereditary form of Parkinson’s disease (PD). The gene encodes a-synuclein, a pre-synaptic protein whose function in the brain is as yet unknown. The mutation was found by linkage studies of a large Italian kindred in which the mean age of onset of PD is 43. The missense mutation is inherited in an autosomal dominant fashion, with a penetrance of approximately 85%, and consists of a single substitution of threonine for alanine at amino acid 53. This substitution is normally found in rodents, who do not spontaneously develop Parkinson’s disease, suggesting that one or more factors found in humans but not rodents may be required for disease expression. Polymeropoulos and colleagues indicate that this mutation is unlikely to account for the majority of either familial or sporadic cases of PD, but is nevertheless of great potential importance to understanding the underlying mechanisms of neurodegeneration in PD.
In several past studies, a gene on chromosome 22 for a cytochrome P450 mono-oxygenase known as CYP2D6 has been tentatively linked to Parkinson’s disease. A recent study by Wilhelmsen and colleagues finds to the contrary and suggests that the presence of a nearby genetic locus on chromosome 22 may have imparted the mistaken impression that CYP2D6 was a PD susceptibility gene. This phenomenon, known as linkage dysequilibrium, occurs when two genetic loci are located close to one another on the same chromosome and are consequently inherited together frequently. Under such circumstances, a linkage study can suggest that a given gene is associated with a disease when, in fact, its nearby neighbor is the actual culprit. In this case, mapping studies of 121 patients with idiopathic Parkinson’s disease and 138 elderly controls failed to find an association between CYP2D6 and PD but did reveal a possible allelic association with two markers near this gene. The study’s case-control design prohibits making a definitive statement that a genetic locus for sporadic PD has been found, but should motivate further studies of the more than 50 genes found in that region of chromosome 22.
COMMENTARY
With the discovery of the disease-causing autosomal dominant missense mutation in the a-synuclein gene on chromosome 4, Parkinson’s disease joins the ranks of neurodegenerative disorders such as Huntington’s, Alzheimer’s, and frontotemporal dementia that have proven genetic underpinnings. The possible association of a chromosome 22 locus with sporadic PD, and the knowledge that toxic factors such as MPTP exposure can precipitate nigral cell loss mimicking idiopathic PD, make it likely that PD, like Alzheimer’s, will prove to be a complex genetic disorder arising from the interaction of one or more genes and environmental factors. DNA-based tests may, therefore, someday prove useful in predicting and diagnosing PD, and, ultimately, new treatment strategies may follow from this discovery. nrr
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