title: Role of the 5-HTTLPR and SNP Promoter Polymorphisms on Serotonin Transporter Gene Expression: a Closer Look at Genetic Architecture and In Vitro Functional Studies of Common and Uncommon Allelic Variants.
abstract: The serotonin (5-hydroxytriptamine (5-HT)) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats (VNTR) located in the promoter region of the human 5-HTT-encoding gene SLC6A4. This length polymorphism gives rise to different promoter variants, variously influencing SLC6A4 expression. Over the years, an extensive literature has investigated the relationships between these promoter variants and SLC6A4 gene expression, since these variants have been variously associated to complex neuropsychiatric conditions and traits. In this review, we detail the genetic architecture of the 5-HTTLPR allelic variants reported so far, with a closer look at the two single nucleotide polymorphisms (SNPs) rs25531 and rs25532 that lies in the VNTR and thus increase genetic variability of the SLC6A4 promoter. We summarize the hypothesized molecular mechanisms underlying this variation. We also provide an update on common and uncommon 5-HTTLPR allelic variants reviewing the available data on functional in vitro analysis of their regulatory effect on SLC6A4 gene transcription. Controversial findings are highlighted and critically discussed. A deeper knowledge of the "5-HTTLPR universe" will be useful to better understand the molecular basis of serotonin homeostasis and the pathological basis underlying serotonin-related neuropsychiatric conditions and traits.
authors.affiliation: National Research Council (CNR), Institute of Translational Pharmacology (IFT), via Fosso del Cavaliere 100, 00133, Rome, Italy. sandra.iurescia@cnr.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Iurescia
authors.affiliation: Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.affiliation: National Research Council (CNR), Institute of Translational Pharmacology (IFT), via Fosso del Cavaliere 100, 00133, Rome, Italy. monica.rinaldi@ift.cnr.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Rinaldi
mesh_terms: D000483:Alleles; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D018598:Minisatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins
keywords: 5-HTT promoter polymorphism; 5-HTTLPR; Allelic variants; In vitro functional studies; SNPs; Serotonin transporter