The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

• MeSH
• Phenotype MeSH
• Haplotypes MeSH
• Attention Deficit Disorder with Hyperactivity * genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Dopamine Plasma Membrane Transport Proteins * genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Dopamine Plasma Membrane Transport Proteins * MeSH
• SLC6A3 protein, human MeSH Browser

Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD.

• MeSH
• Cell Nucleus metabolism   MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• Dopaminergic Neurons metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Substance-Related Disorders etiology   genetics   MeSH
• Dopamine Plasma Membrane Transport Proteins genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• Sex Factors MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• HIVEP2 protein, human MeSH Browser
• Hivep2 protein, mouse MeSH Browser
• Hivep2 protein, rat MeSH Browser
• Dopamine Plasma Membrane Transport Proteins MeSH
• SLC6A3 protein, human MeSH Browser
• Slc6a3 protein, mouse MeSH Browser
• Slc6a3 protein, rat MeSH Browser
• Transcription Factors MeSH