Dopamine 2-hydroxylase (DBH) catalyzes synthesis of the neurotransmitter norepinephrine (NE) from dopamine (DA), and thereby regulates levels of both molecules. DBH is detectable in human serum, where its activity largely reflects sequence variation at the structural locus DBH. We identified a single nucleotide polymorphism (SNP) 970 bp upstream of the transcriptional start site (-970C>T) that accounts for 30-50% of the total variance in serum DBH activity, with the "T" allele being associated with lower activity than the "C" allele, in a co-dominant pattern. Our work on a population-genetic level, and molecular experiments from another laboratory provide strong evidence that -970C>T is a true regulatory variant, affecting transcription of DBH. However, the molecular experiments suggested that the low-serum-DBH T allele associates with greater transcription. Thus, how -970C>T regulates DBH expression in vivo is not clear. The present project proposes to use BAC transgenesis, followed by crossing with Dbh -/- mice lacking endogenous DBH expression, to investigate DBH expression in brain, adrenal medulla and serum, associated with either the T or C allele in an otherwise identical human-sequence context of ~170 kb. This project will inform multiple areas of public health research, including studies of psychosis, mood disorders, drug addiction, neuro-degenerative disorders, and disorders of human blood pressure, as variation in serum DBH and/or -970C>T associates with important aspects of human phenotypes related to all of those disorders. The proposed work will produce a valuable and innovative animal model for investigation of many aspects of genetic variation in NE-mediated neurotransmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS072712-02
Application #
8298987
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Mamounas, Laura
Project Start
2011-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$191,688
Indirect Cost
$66,688
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322