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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

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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.

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Acknowledgments

We are particularly grateful to D. Fioretti for helping us with nucleotide sequence alignment and statistical analysis and to I. Condò for helpful and constructive comments on our in vitro functional studies. We thank Mrs C. Gravina and M. Urbano, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, I.R.C.C.S. “Casa Sollievo della Sofferenza” for their skilled technical works.

We also thank Dr. N. Di Simone, Università Cattolica del Sacro Cuore, Rome, Italy, for providing us with the JAR cell line.

Results described in this review were included in a thesis entitled “Identification and functional characterization of promoter allelic variants of the human serotonin transporter gene” submitted for fulfilment of the Master of Science in Human Biology and Evolution by Elena De Dominicis at the University of Rome Tor Vergata.

This work was supported by “Ministero della Salute”, I.R.C.C.S. Research Program, Ricerca Corrente 2015–2017, Linea n. 2 “Malattie complesse e terapie innovative” and by the “5 × 1000” voluntary contribution.

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The authors declare that they have no conflict of interest to disclose.

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Correspondence to Sandra Iurescia or Monica Rinaldi.

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Davide Seripa and Monica Rinaldi shared senior authorship

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Iurescia, S., Seripa, D. & Rinaldi, M. 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. Mol Neurobiol 53, 5510–5526 (2016). https://doi.org/10.1007/s12035-015-9409-6

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  • DOI: https://doi.org/10.1007/s12035-015-9409-6

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