Human Molecular Genetics Advance Access originally published online on December 8, 2005
Human Molecular Genetics 2006 15(2):299-305; doi:10.1093/hmg/ddi445
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Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women
1Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10028, USA, 2Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA 90095, USA and 3The Galton Laboratory, University College London, UK
* To whom correspondence should be addressed at: Department of Psychiatry, Weill Medical College of Cornell University, Room LC907A, Box 244, 1300 York Avenue, New York, NY 10021, USA. Tel: +1 2127466723; Fax: +1 2127468529; Email: ceg2004{at}med.cornell.edu
Received October 21, 2005; Accepted November 28, 2005
The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.
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