Affinage

SLC6A4

Sodium-dependent serotonin transporter · UniProt P31645

Round 2 corrected
Length
630 aa
Mass
70.3 kDa
Annotated
2026-04-28
130 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC6A4 encodes the sodium- and chloride-dependent serotonin transporter (SERT), a 630-amino-acid, 12-transmembrane-segment protein that mediates high-affinity reuptake of 5-HT from the extracellular space in both the central nervous system and peripheral tissues, thereby terminating serotonergic signaling (PMID:7681602, PMID:7684072). X-ray crystallography of human SERT at 3.15 Å resolution shows that SSRI antidepressants lock the transporter in an outward-open conformation by occupying a central substrate-binding site between TM1/3/6/8/10, while an allosteric vestibular site sterically impedes drug unbinding (PMID:27049939). Transcription from SLC6A4 is regulated by the functionally triallelic 5-HTTLPR/rs25531 promoter polymorphism, where the L(A) allele drives ~2-fold higher expression than the S or L(G) alleles, and by an intron 2 VNTR whose activity is modulated by YB-1 binding opposed by CTCF (PMID:16642437, PMID:15229244). Loss of SERT function—whether by the low-expressing S allele, genetic knockout, or pharmacological inhibition—results in amygdala hyperreactivity, uncoupling of amygdala–anterior cingulate fear-extinction circuitry, and amplified prefrontal 5-HT1A receptor signaling via loss of Src-family tyrosine kinase–dependent inhibitory control (PMID:15880108, PMID:21818344, PMID:24760870).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1993 High

    Molecular cloning of human SERT from placenta and platelets established that a single gene on chromosome 17q encodes a 630-aa, 12-TM protein responsible for Na⁺/Cl⁻-dependent, antidepressant-sensitive 5-HT reuptake in both brain and periphery, resolving the molecular identity of the serotonin transporter.

    Evidence cDNA cloning, HeLa cell reconstitution with radiotracer uptake and pharmacological inhibition, somatic cell hybrid mapping

    PMID:7681602 PMID:7684072

    Open questions at the time
    • Post-translational modifications predicted from sequence but not functionally validated
    • Oligomeric state in native membranes unknown
    • Three-dimensional structure unresolved
  2. 1996 High

    Identification of the 5-HTTLPR promoter polymorphism demonstrated that common genetic variation directly modulates SLC6A4 transcription, with the long allele conferring ~2–3-fold higher expression than the short allele, providing the first functional regulatory variant for the serotonin system.

    Evidence Luciferase reporter assays in serotonergic and non-serotonergic cells, lymphoblast expression analysis

    PMID:8632190

    Open questions at the time
    • Chromatin context and in vivo transcription rates not assessed
    • Effect of the intron 2 VNTR on expression not yet mechanistically dissected
    • Whether S-allele effect is cell-type-specific was untested
  3. 2004 High

    Converging neuroimaging and molecular studies showed that the low-expressing S allele reduces cingulate/amygdala gray matter volume and uncouples the amygdala–anterior cingulate feedback circuit during fear processing, while molecular work identified YB-1 and CTCF as antagonistic transcription factors mediating allele-dependent expression at the intron 2 VNTR, establishing both neural systems-level and molecular mechanisms for genetic risk.

    Evidence Structural MRI and fMRI functional connectivity in large cohorts; yeast one-hybrid, EMSA, and reporter assays for VNTR regulators; mucosal biopsy qRT-PCR and immunohistochemistry in GI disease

    PMID:15188158 PMID:15229244 PMID:15592465 PMID:15880108

    Open questions at the time
    • Causal direction from genotype to circuit phenotype not established (observational imaging)
    • YB-1/CTCF mechanism demonstrated with reporters but not at endogenous locus
    • Mechanism of mucosal SERT downregulation in IBS/UC not identified
  4. 2006 High

    Discovery that rs25531 renders 5-HTTLPR functionally triallelic—with L(G) equivalent to S—refined the genetic architecture of SLC6A4 expression and linked the high-expressing L(A)/L(A) genotype to OCD risk, demonstrating that SERT overexpression, not only underexpression, can be pathogenic.

    Evidence Luciferase reporter assays in raphe-derived cells, allele-specific expression across 62 lymphoblastoid lines, transmission disequilibrium test in OCD trios

    PMID:16642437

    Open questions at the time
    • No direct measurement of synaptic 5-HT clearance by genotype in human brain
    • OCD association not yet replicated in large independent cohorts at time of publication
    • How overexpression leads to OCD-spectrum phenotypes mechanistically was unresolved
  5. 2011 High

    Serotonin transporter knockout mice exhibited impaired fear extinction recall with increased amygdala–prefrontal theta synchrony, causally linking SERT loss to oscillatory dysfunction in the fear-extinction circuit and going beyond the correlational human imaging data.

    Evidence 5-HTT knockout mice with simultaneous local field potential recordings in lateral amygdala and mPFC during fear conditioning

    PMID:21818344

    Open questions at the time
    • Whether circuit phenotype is developmental or acute consequence of SERT loss is unresolved
    • Rescue by SERT re-expression not performed
    • Translational relevance to human S-allele carriers is indirect
  6. 2014 High

    Electrophysiology in prefrontal cortex slices from 5-HTT-deficient mice identified a specific intracellular mechanism: loss of SERT amplifies 5-HT1A receptor–Kir3 channel coupling through reduced Src-family tyrosine kinase–dependent inhibitory control, explaining how transporter loss reshapes postsynaptic serotonergic signaling.

    Evidence Whole-cell patch-clamp in PFC slices from KO and neonatal fluoxetine-treated mice, pharmacological manipulation of tyrosine kinases and phosphatases

    PMID:24760870

    Open questions at the time
    • Specific Src-family kinase isoform responsible not identified
    • Whether this mechanism operates in human cortex is untested
    • Relationship between amplified 5-HT1A signaling and behavioral phenotypes not directly demonstrated
  7. 2016 High

    The first X-ray crystal structures of human SERT resolved the atomic basis of antidepressant action: SSRIs occupy a central substrate-binding site between TM helices to lock an outward-open state, while an allosteric vestibular site explains the slow off-rate of (S)-citalopram, providing a structural framework for drug design.

    Evidence 3.15 Å X-ray crystallography of thermostabilized human SERT co-crystallized with (S)-citalopram and paroxetine

    PMID:27049939

    Open questions at the time
    • Structures captured only outward-open state; inward-open and occluded conformations unresolved
    • Substrate (5-HT)-bound structure not obtained
    • Thermostabilizing mutations may alter conformational dynamics

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the complete transport cycle structural dynamics (inward-open, occluded states with substrate), the cell-type-specific mechanisms governing mucosal SERT downregulation in gastrointestinal disease, whether SERT oligomerization is functionally required for transport in vivo, and the causal chain from 5-HTTLPR genotype through circuit-level phenotypes to psychiatric disease risk in humans.
  • No substrate-bound or inward-facing structural state resolved
  • SERT oligomeric stoichiometry and functional relevance in native membranes uncharacterized
  • Causal genotype-to-disease pathway remains incompletely bridged in humans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-382551 Transport of small molecules 3
Partners
CTCFYBX1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The human serotonin transporter (SERT/SLC6A4) was molecularly cloned from placenta, revealing a 630-amino acid protein with 12 predicted transmembrane segments, Na⁺- and Cl⁻-dependent high-affinity serotonin transport (Km ~463 nM), and sensitivity to antidepressants (paroxetine, fluoxetine, imipramine) and cocaine/amphetamine. The gene was mapped to chromosome 17q11.1–17q12 and shown to encode both brain and platelet 5-HT transporters. cDNA cloning, transfection into HeLa cells, radiotracer uptake assay, pharmacological inhibition, somatic cell hybrid mapping, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 7681602
1993 The primary structure of human platelet SERT (SLC6A4) is identical to the brain serotonin transporter, encoded by a single gene on chromosome 17. The 630-aa protein contains two putative N-glycosylation sites in the second extracellular loop, consensus phosphorylation sites for cAMP-dependent protein kinase in the N-terminal cytoplasmic region, and three potential PKC phosphorylation sites. PCR-based cDNA cloning and sequencing, hydropathicity analysis, chromosomal assignment Journal of neurochemistry High 7684072
1994 The human SLC6A4 gene spans approximately 31 kb and is composed of 14 exons. A variable number tandem repeat (VNTR) polymorphism was identified within the gene, providing the first structural framework for genetic studies of serotonin transporter regulation. Genomic library screening, exon mapping, DNA sequencing Journal of neural transmission. General section High 7865169
1996 A polymorphic repetitive element in the 5'-flanking transcriptional regulatory region of SLC6A4 (5-HTTLPR) drives allele-dependent differential promoter activity: the long (L) allele confers approximately 2–3-fold higher basal transcription and 5-HT transporter expression than the short (S) allele in transfected cells and lymphoblasts, establishing this as a functional regulatory variant. Reporter gene (luciferase) transfection assays in serotonergic and non-serotonergic cells, lymphoblast 5-HTT expression analysis Journal of neurochemistry High 8632190
1996 The recombinant rat serotonin transporter SERT1 expressed in HEK293 cells forms oligomeric complexes: treatment with sulfhydryl-oxidizing agents and the homobifunctional cross-linker DMS generated adducts of 130–180 kDa and 220–270 kDa, indicating that the membrane-bound transporter has a quaternary oligomeric structure. Transient transfection in HEK293 cells, chemical cross-linking (dimethyl suberimidate), SDS-PAGE/immunoblot FEBS letters Medium 8925924
1996 The STin2 VNTR in intron 2 of SLC6A4 is a polymorphic transcriptional regulatory element; the nine-copy repeat allele (STin2.9) is significantly associated with unipolar depressive disorder, providing the first evidence that intronic variation in SLC6A4 may affect gene expression and disease risk. PCR genotyping, case-control association study, allele frequency comparison Lancet Low 8602004
2004 The SLC6A4 intron 2 VNTR is a transcriptional regulatory domain whose allelic variants drive differential reporter gene expression in vivo and in vitro. Yeast one-hybrid screening identified the transcription factor YB-1 as a sequence-specific VNTR-binding activator; CTCF (CCTC-binding factor) blocks YB-1 binding to VNTR sequences and antagonizes YB-1-directed reporter expression, providing a molecular mechanism for allele-dependent differential transcription. Yeast one-hybrid screening, reporter gene assays, electrophoretic mobility shift assay (EMSA), in vitro binding assays The Journal of neuroscience High 15229244
2004 Mucosal serotonin transporter (SERT) mRNA and protein are significantly reduced in patients with ulcerative colitis, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C), without a corresponding decrease in enterochromaffin cell numbers or basal/stimulated 5-HT release, implicating defective 5-HT reuptake via SLC6A4 as an intrinsic gastrointestinal molecular defect in these disorders. Rectal biopsy analysis, quantitative RT-PCR for SERT mRNA, immunohistochemistry for SERT protein, 5-HT release assays Gastroenterology High 15188158
2004 The 5-HTTLPR short allele of SLC6A4 is associated with reduced gray matter volume in perigenual anterior cingulate cortex and amygdala, and with relative uncoupling of the amygdala–cingulate feedback circuit during processing of fearful stimuli. The magnitude of amygdala-cingulate coupling inversely predicted ~30% of variation in temperamental anxiety, establishing a developmental, systems-level neural mechanism for the genetic susceptibility conferred by the short allele. Multimodal neuroimaging (structural MRI volumetry + fMRI functional connectivity), large healthy-subject cohort (N≈114) Nature neuroscience High 15880108
2004 Carriers of the SLC6A4 short allele show stronger amygdala activation and greater functional coupling between amygdala and ventromedial prefrontal cortex during presentation of aversive stimuli compared with long-allele homozygotes, directly linking SERT genotype to amygdala-prefrontal serotonergic circuitry. fMRI (BOLD), genotyping of 5-HTTLPR, passive viewing of aversive vs. neutral pictures Nature neuroscience High 15592465
2006 The 5-HTTLPR is functionally triallelic: a common G→A substitution (rs25531) within the L allele creates an AP2 transcription-factor binding site, converting the L allele into a low-expressing L(G) allele functionally equivalent to the S allele. Expression assays in 62 lymphoblastoid cell lines demonstrated codominant allele action, with the L(A)/L(A) genotype conferring highest expression (~2-fold over S or L(G)). The gain-of-function L(A)/L(A) genotype was ~2-fold more common in OCD patients, establishing SERT overexpression as a risk mechanism for OCD. Luciferase reporter assays in raphe-derived cells, allele-specific expression in 62 lymphoblastoid lines, case-control genotyping (OCD probands + trios), transmission disequilibrium test American journal of human genetics High 16642437
2006 ITGB3 (integrin beta-3) and SLC6A4 expression levels are correlated (r = 0.38–0.78) in murine and human datasets, and genetic variation in ITGB3 is associated with expression of both ITGB3 (P=0.012) and SLC6A4 (P=0.008), suggesting that ITGB3 acts as a trans-regulator of SLC6A4 expression and that epistatic interaction between the two genes influences serotonin levels. Public expression database analysis (murine and human), eQTL analysis in CEPH individuals, genetic association Human genetics Low 16721604
2008 SLC6A4 (5-HTTLPR S allele) and BDNF (Val66Met) exhibit biological epistasis at the neural systems level: the BDNF Met allele (which reduces BDNF secretion and 5-HT responsivity) protects against S-allele-driven volume reduction of the subgenual anterior cingulate cortex and against reduced structural connectivity between amygdala and anterior cingulate, demonstrating a gene–gene interaction between serotonergic and neurotrophic signaling pathways in emotion circuitry. Structural MRI volumetry and diffusion tensor imaging (structural connectivity) in healthy subjects (N=111), two-way ANOVA for genotype interaction Molecular psychiatry Medium 18347599
2011 5-HTT-deficient (SLC6A4 knockout) mice show impaired recall of conditioned fear extinction and delayed extinction learning, accompanied by increased theta synchronization between the lateral amygdala and infralimbic medial prefrontal cortex during extinction, establishing a causal role for SERT in amygdala-prefrontal circuit oscillatory dynamics underlying fear regulation. 5-HTT knockout mouse model, Pavlovian fear conditioning, simultaneous local field potential recordings in lateral amygdala and mPFC, resident-intruder social defeat paradigm PloS one High 21818344
2013 Gain-of-function SERT alleles (high-expressing 5-HTTLPR L(A) allele and the rare coding variant I425V) are enriched in Tourette's disorder probands, with I425V found at 1.57% in OCD/TD spectrum vs. 0.15% in controls, indicating that SERT overactivity (not just underactivity) contributes to serotonergic abnormalities in TD. Case-control genotyping (N=151 TD probands, N=858 controls), triallelic 5-HTTLPR/rs25531/rs25532 haplotyping, rare variant (I425V) sequencing Movement disorders Medium 23630162
2014 Mice with compromised 5-HTT function (genetic deletion or neonatal SSRI treatment) exhibit amplified 5-HT1A receptor-mediated inhibitory currents in prefrontal pyramidal neurons, with enhanced downstream coupling to Kir3 channels. This hyperresponsiveness is due to loss of tyrosine kinase-dependent inhibitory control: in wild-type mice, Src family tyrosine kinase inhibition mimics the amplified 5-HT1A response, while tyrosine phosphatase inhibition reduces it in 5-HTT-deficient mice. Whole-cell patch-clamp electrophysiology in prefrontal cortex slices, 5-HTT knockout mice, neonatal fluoxetine treatment, pharmacological manipulation of tyrosine kinases and phosphatases The Journal of neuroscience High 24760870
2016 X-ray crystallographic structures of human SERT (SLC6A4) at 3.15 Å resolution bound to antidepressants (S)-citalopram or paroxetine reveal that these drugs lock SERT in an outward-open conformation by occupying the central binding site between TM helices 1, 3, 6, 8, and 10, directly blocking serotonin access. An allosteric site was identified at the periphery of the extracellular vestibule between EL4/EL6 and TM1/6/10/11; occupancy of this site sterically hinders ligand unbinding from the central site, explaining (S)-citalopram's allosteric action. X-ray crystallography of thermostabilized human SERT at 3.15 Å, co-crystallization with (S)-citalopram and paroxetine, structure–function analysis Nature High 27049939
2018 The Gulf toadfish SERT (SLC6A4 ortholog) encodes a 673-aa protein with 83% similarity to zebrafish SERT. When expressed in Xenopus oocytes, it demonstrates Na⁺/Cl⁻-dependent serotonin transport with a Km of 2.08 μmol/l, similar to zebrafish and human SERT. Systemic SSRI (fluoxetine) administration dose-dependently increases plasma 5-HT, indicating that peripheral SERT normally maintains low circulating 5-HT in teleosts lacking platelets. cRNA expression in Xenopus oocytes, radiotracer uptake kinetics, in vivo fluoxetine administration with plasma 5-HT measurement The Journal of experimental biology High 29487159

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science (New York, N.Y.) 4885 12869766
1996 Allelic variation of human serotonin transporter gene expression. Journal of neurochemistry 1731 8632190
2002 Serotonin transporter genetic variation and the response of the human amygdala. Science (New York, N.Y.) 1573 12130784
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2005 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature neuroscience 1391 15880108
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2009 Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 1107 19531786
2011 The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry 942 21199959
2006 Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. American journal of human genetics 918 16642437
2010 Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. The American journal of psychiatry 898 20231323
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
1993 Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proceedings of the National Academy of Sciences of the United States of America 737 7681602
2009 Candidate gene studies of ADHD: a meta-analytic review. Human genetics 713 19506906
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 613 15188158
2005 A susceptibility gene for affective disorders and the response of the human amygdala. Archives of general psychiatry 570 15699291
2005 The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Archives of general psychiatry 558 15867106
2016 X-ray structures and mechanism of the human serotonin transporter. Nature 530 27049939
2007 Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biological psychiatry 527 17949693
2004 Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature neuroscience 509 15592465
1994 Organization of the human serotonin transporter gene. Journal of neural transmission. General section 508 7865169
2004 Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the United States of America 503 15563601
1993 Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. Journal of neurochemistry 471 7684072
2004 Gene-environment interaction analysis of serotonin system markers with adolescent depression. Molecular psychiatry 460 15241435
2006 Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological psychiatry 453 16458264
2006 Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular psychiatry 440 16402131
2004 Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 440 15108187
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1996 Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet (London, England) 437 8602004
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2019 Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 383 31666698
2019 No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples. The American journal of psychiatry 378 30845820
1997 Serotonin transporter (5-HTT) gene variants associated with autism? Human molecular genetics 199 9361027
2008 Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Molecular psychiatry 183 18347599
2017 The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington's disease patients. Scientific reports 171 28465506
2008 How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology 167 18824000
2019 Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease. Nature medicine 155 31263285
2014 HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation. Brain : a journal of neurology 153 24459107
2006 Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. Molecular psychiatry 129 16969368
2009 Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. The American journal of psychiatry 111 19487392
2019 FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat. Human molecular genetics 106 30358836
1998 Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. American journal of medical genetics 105 9514579
2005 AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance. PLoS genetics 104 16205790
2007 Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Human genetics 100 17203304
2017 Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex. The EMBO journal 98 29212816
2011 Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice. PloS one 95 21818344
2012 Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. Journal of controlled release : official journal of the Controlled Release Society 91 22921802
2004 Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry research 90 15450911
2019 Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 88 31015293
2008 Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy. The pharmacogenomics journal 79 18253134
2013 An N-terminal nuclear export signal regulates trafficking and aggregation of Huntingtin (Htt) protein exon 1. The Journal of biological chemistry 73 23319588
2014 The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression. Journal of psychiatric research 72 24657235
2021 Small molecule splicing modifiers with systemic HTT-lowering activity. Nature communications 70 34911927
2011 Differential effects of prenatal stress in 5-Htt deficient mice: towards molecular mechanisms of gene × environment interactions. PloS one 69 21857948
2015 DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli. Journal of psychiatry & neuroscience : JPN 68 25825812
2018 N-terminal Huntingtin (Htt) phosphorylation is a molecular switch regulating Htt aggregation, helical conformation, internalization, and nuclear targeting. The Journal of biological chemistry 67 30185623
2016 Serotonin Transporter Gene (SLC6A4) Methylation Associates With Neonatal Intensive Care Unit Stay and 3-Month-Old Temperament in Preterm Infants. Child development 67 26822441
2009 Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology 67 19776381
2013 A longitudinal study of SLC6A4 DNA promoter methylation and poststroke depression. Journal of psychiatric research 64 23702251
2008 Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Molecular psychiatry 63 18663369
2004 YB-1 and CTCF differentially regulate the 5-HTT polymorphic intron 2 enhancer which predisposes to a variety of neurological disorders. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 15229244
2009 5-HTT genotype effect on prefrontal-amygdala coupling differs between major depression and controls. Psychopharmacology 57 19387615
2008 The effect of 5-HTT gene promoter polymorphism on impulsivity depends on family relations in girls. Progress in neuro-psychopharmacology & biological psychiatry 56 18495314
2007 A genetic association study of 5-HTT LPR and GNbeta3 C825T polymorphisms with irritable bowel syndrome. Neurogastroenterology and motility 54 17564628
1996 The membrane-bound rat serotonin transporter, SERT1, is an oligomeric protein. FEBS letters 54 8925924
2021 Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels. Autophagy 51 34024231
2020 Increased methylation of NR3C1 and SLC6A4 is associated with blunted cortisol reactivity to stress in major depression. Neurobiology of stress 49 33344725
2010 pARIS-htt: an optimised expression platform to study huntingtin reveals functional domains required for vesicular trafficking. Molecular brain 48 20515468
2018 Multiple clinical features of Huntington's disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. Journal of neurology 47 29956026
2022 An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. Nature communications 46 36357392
2012 Serotonin transporter gene (SLC6A4) polymorphism in patients with irritable bowel syndrome and healthy controls. Journal of gastrointestinal and liver diseases : JGLD 46 22457857
2011 Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 21994396
2013 5-HTT deficiency affects neuroplasticity and increases stress sensitivity resulting in altered spatial learning performance in the Morris water maze but not in the Barnes maze. PloS one 45 24167611
2006 LEPR, ADBR3, IRS-1 and 5-HTT genes polymorphisms do not associate with obesity. Endocrine journal 45 17124363
2021 Hidden pandemic: COVID-19-related stress, SLC6A4 methylation, and infants' temperament at 3 months. Scientific reports 44 34341434
2015 Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Scientific reports 44 26218986
2009 Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds. Journal of pediatric psychology 44 19779024
2006 Stressful life events, 5-HTT genotype and risk of depression. The British journal of psychiatry : the journal of mental science 43 16507957
2018 BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1. Psychiatry research 41 30529315
2014 Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. Translational psychiatry 38 25335169
2015 Epidemiology of Huntington disease: first post-HTT gene analysis of prevalence in Italy. Clinical genetics 37 25689972
2013 Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. Movement disorders : official journal of the Movement Disorder Society 37 23630162
2019 Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease. Neurobiology of aging 36 31810584
2013 Multi-cultural association of the serotonin transporter gene (SLC6A4) with substance use disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36 23518607
2006 ITGB3 shows genetic and expression interaction with SLC6A4. Human genetics 35 16721604
2018 Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes. Brain : a journal of neurology 34 29608652
2014 Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance? Behavioural brain research 33 24815315
2022 Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens. Nature communications 32 35082301
2015 Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study. Journal of affective disorders 32 25889020
2017 Interplay between maternal Slc6a4 mutation and prenatal stress: a possible mechanism for autistic behavior development. Scientific reports 31 28821725
2007 Serotonin transporter gene (5-Htt): association analysis with temporal lobe epilepsy. Neuroscience letters 31 17548158
2000 Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neuroscience letters 31 10771175
2022 Alternative processing of human HTT mRNA with implications for Huntington's disease therapeutics. Brain : a journal of neurology 29 35793238
2022 Interaction of huntingtin with PRMTs and its subsequent arginine methylation affects HTT solubility, phase transition behavior and neuronal toxicity. Human molecular genetics 28 34888656
2017 Epigenetic adaptation of the placental serotonin transporter gene (SLC6A4) to gestational diabetes mellitus. PloS one 28 28650965
2014 SLC6A4 markers modulate platelet 5-HT level and specific behaviors of autism: a study from an Indian population. Progress in neuro-psychopharmacology & biological psychiatry 28 25261775
2016 SLC6A4 promoter region methylation and socio-emotional stress response in very preterm and full-term infants. Epigenomics 27 27381173
2022 Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT. Nature communications 26 35948542
2015 Association of serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder: A preliminary study. The Indian journal of medical research 25 26261165
2007 Bad nature, bad nurture, and testimony regarding MAOA and SLC6A4 genotyping at murder trials. Journal of forensic sciences 25 17944904
2019 A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease. American journal of human genetics 24 31708117
2022 Maternal and infant NR3C1 and SLC6A4 epigenetic signatures of the COVID-19 pandemic lockdown: when timing matters. Translational psychiatry 23 36114180
2020 Huntington's Disease-An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components. Cells 23 32580314
2014 SLC6A4 polymorphism, population genetics, and psychiatric traits. Human genetics 22 24385047
2013 Association of serotonin transporter gene (SLC6A4) polymorphisms with schizophrenia susceptibility and symptoms in a Chinese-Han population. Progress in neuro-psychopharmacology & biological psychiatry 21 23583772
2013 A serotonin transporter gene (SLC6A4) polymorphism is associated with reduced risk of irritable bowel syndrome in American and Asian population: a meta-analysis. PloS one 21 24069428
2022 A novel and accurate full-length HTT mouse model for Huntington's disease. eLife 20 35023827
2018 Epigenetic variation at the SLC6A4 gene promoter in mother-child pairs with major depressive disorder. Journal of affective disorders 20 30447571
2017 Association analysis of SLC6A4 and HTR2A genes with obsessive-compulsive disorder: Influence of the STin2 polymorphism. Comprehensive psychiatry 20 29331882
2014 Association study of serotonin transporter SLC6A4 gene with Chinese Han irritable bowel syndrome. PloS one 20 24392134
2013 Serotonergic genes (5-HTT and HTR1A) and separation life events: gene-by-environment interaction for panic disorder. Neuropsychobiology 20 23635830
2007 Monoamine metabolites level in CSF is related to the 5-HTT gene polymorphism in treatment-resistant depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20 17299512
2021 Role of NR3C1 and SLC6A4 methylation in the HPA axis regulation in burnout. Journal of affective disorders 18 34509065
2018 Association between the SLC6A4 gene and schizophrenia: an updated meta-analysis. Neuropsychiatric disease and treatment 18 30643413
2008 Emotion-induced retrograde amnesia is determined by a 5-HTT genetic polymorphism. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 18614671
2024 Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype. European journal of human genetics : EJHG 17 38433266
2013 Gender-specific association of the SLC6A4 and DRD2 gene variants in bipolar disorder. The international journal of neuropsychopharmacology 17 24229495
2010 Interaction of SLC6A4 and DRD2 polymorphisms is associated with a history of delirium tremens. Addiction biology 17 20002020
2018 Modulation of Fear and Arousal Behavior by Serotonin Transporter (5-HTT) Genotypes in Newly Hatched Chickens. Frontiers in behavioral neuroscience 16 30524254
2017 REVIEW-ARTICLE Intermediate alleles of Huntington's disease HTT gene in different populations worldwide: a systematic review. Genetics and molecular research : GMR 16 28387881
2015 A meta-analysis of the associations between the SLC6A4 promoter polymorphism (5HTTLPR) and the risk for alcohol dependence. Psychiatric genetics 16 25710844
2019 Downregulation of Orco and 5-HTT Alters Nestmate Discrimination in the Subterranean Termite Odontotermes formosanus (Shiraki). Frontiers in physiology 15 31244679
2019 Extensive Expression Analysis of Htt Transcripts in Brain Regions from the zQ175 HD Mouse Model Using a QuantiGene Multiplex Assay. Scientific reports 15 31695145
2019 Nucleation Inhibition of Huntingtin Protein (htt) by Polyproline PPII Helices: A Potential Interaction with the N-Terminal α-Helical Region of Htt. Biochemistry 15 31814404
2016 The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing. Cell death & disease 15 27124581
2015 Genetic Polymorphism of the Serotonin Transporter Gene, SLC6A4 rs16965628, Is Associated with Obsessive Compulsive Disorder. Genetic testing and molecular biomarkers 15 25751280
2022 HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury. Autophagy 14 36048753
2021 Association of SLC6A4 methylation with long-term outcomes after stroke: focus on the interaction with suicidal ideation. Scientific reports 14 33526821
2018 Molecular and functional characterization of the Gulf toadfish serotonin transporter SLC6A4. The Journal of experimental biology 14 29487159
2014 Mice with compromised 5-HTT function lack phosphotyrosine-mediated inhibitory control over prefrontal 5-HT responses. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 24760870