Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity

Rungnapa Hirunsatit, Elizabeth D. George, Barbara K. Lipska, Hani M. Elwafi, Lisa Sander, Carolyn M. Yrigollen, Joel Gelernter, Elena L. Grigorenko, Jaakko Lappalainen, Shrikant Mane, Angus C. Nairn, Joel E. Kleinman, Arthur A. Simen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Objective Sodium-dependent and chloride-dependent γ-aminobutyric acid (GABA) transporter 1 (SLC6A1) is the target of a number of drugs of clinical importance and is a major determinant of synaptic GABA concentrations. We resequenced the human SLC6A1 gene previously and discovered a novel 21 bp insertion in the predicted promoter region that creates a second tandem copy of the sequence. Here we sought to determine the functional relevance of this variation. Methods We used reporter assays, mobility shift assays, quantitative PCR, and proteomics methods as well as postmortem expression analysis for this work. Results Reporter assays showed that the insertion allele significantly increases promoter activity in multiple cell lines. The zinc finger transcription factor ZNF148 was found to significantly transactivate the promoter and increase expression when overexpressed but could not account for the differences in activity between the two alleles of the promoter. Copy number of the insertion sequence was associated with exponentially increasing activity of a downstream promoter, suggesting that the insertion sequence has enhancer activity when present in multiple copies. SLC6A1 promoter genotype was found to predict SLC6A1 RNA expression in human postmortem hippocampal samples. These results suggest that the insertion polymorphism leads to increased SLC6A1 promoter activity because, in part, of creation of an enhancer element when present as multiple copies. Genotyping individuals from Tanzania in this study suggested that the insertion allele has its origin in Africa. Conclusion On account of the effect of the insertion on promoter activity, this relatively common polymorphism may prove useful in predicting clinical response to pharmacological modulators of SLC6A1 as well as GABAergic function in individuals of African descent Pharmacogenetics and Genomics 19:53-65

Original languageEnglish (US)
Pages (from-to)53-65
Number of pages13
JournalPharmacogenetics and Genomics
Issue number1
StatePublished - Jan 2009
Externally publishedYes


  • African continental ancestry group
  • Enhancer elements
  • Transcription factors
  • Zinc fingers
  • γ-aminobutyric acid plasma membrane transport proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Genetics(clinical)


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