SLC6A4 (solute carrier family 6 member 4)

2019-03-01   Rafig Gurbanov  , Berkay Kalkanci  

Identity

HGNC
LOCATION
17q11.2
IMAGE
Atlas Image
LEGEND
Figure 1. Genomic location of SLC6A4 (Chromosome 17 - NC_000017.11 Reference GRCh38.p12 Primary Assembly)
IMAGE
Atlas Image
LEGEND
Figure 2. Chromosomal Location of SLC6A4. Cytogenetic Location: 17q11.2, which is the long (q) arm of chromosome 17 at position 11.2 (U.S. National Library of Medicine)
LOCUSID
ALIAS
5-HTT,5-HTTLPR,5HTT,HTT,OCD1,SERT,SERT1,hSERT
FUSION GENES

Abstract

The SLC6A4 gene encodes a sodium-dependent serotonin reuptake protein delivering the neurotransmitter serotonin from the synaptic cleft back to the presynaptic end. Its main function is to abort the activity of serotonin and forward it to neurotransmitter pool for recycling. The psychomotor stimulant drugs mainly amphetamines and cocaine act on this transmembrane protein which is a member of the sodium: neurotransmitter symporter family. SLC6A4 gene polymorphisms affect the rate of serotonin reuptake and play an important role in pathogenesis of various illnesses like Sudden infant death syndrome, aggressive behaviour in Alzheimer patients, Seasonal affective disorder, Major depressive Disorder and Obsessive-compulsive disorder.

DNA/RNA

Note

The SLC6A4 gene is 41,684 bp long (according to UCSC, GRCh38/hg38), located on the plus strand and spans 15 exons (NCBI Homo sapiens Annotation Release 109).
Atlas Image
Figure 3. Numbers and illustrative sizes of exons of human SLC6A4. (https:\\www.atlasgeneticsoncology.org)

Transcription

The gene has 5 transcripts (Table 1)
NameTranscript IDbpProtein (aa)    Biotype
SLC6A4-201  ENST00000261707.7  6604  630 aaProtein coding
SLC6A4-202  ENST00000394821.2  2160  618 aaProtein coding
SLC6A4-203  ENST00000401766.6  6543  630 aaProtein coding
SLC6A4-204  ENST00000578609.1  566  No proteinRetained intron
SLC6A4-205  ENST00000579221.5  1069  72 aaNonsense mediated decay

Table 1. Transcripts of human SLC6A4 gene (Ensemble, GRCh38.p12).

Proteins

Note

SLC6A4 gene encodes a serotonin transporter protein (5-HTT) of 70,320 Dalton and composed of 630 amino acids (Figure 4) (Ramamoorthy et al., 1993). The protein belongs to family of neurotransmitter/sodium transporter (NSS). NSS family also includes dopamine, glycine and γ -aminobutyric acid (GABA) transporters (Chen et al., 2004). The members of this family have 12 transmembrane domains and intracellular N and C terminal regions (Yamashita et al., 2005). The large extracellular structure (EL) between TM3 and TM4 is modified by N-linked glycosylation in all eukaryotic NSS proteins and the number of N-linked glycosylation sites can vary from carrier to carrier. The consensus sequence for N-linked glycosylation is N-X-S/T (the amide nitrogen glycan binding region in the asparagine side chain and X is any amino acid except proline) (Mitra et al., 2006). The EL2 of the 5-HTT protein has two glycosylation sites carrying glycan (Tate and Blakely,. 1994). Mutations in the glycosylation sites of 5-HTT and other NSS proteins generally cause problems in the transport of neurotransmitter proteins such as serotonin at the cell surface (Tate and Blakely,.1994 ; Olivares et al., 1995; Melikian et al., 1996; Li et al., 2004).
Atlas Image
Figure 4. Structure of human Solute carrier family 6 member 4. X-ray structure of the ts3 human serotonin transporter complexed with paroxetine (selective serotonin re-uptake inhibitor) at the central site (PDB ID: 5I6X) (https://www.rcsb.org).

Expression

SLC6A4 gene is most commonly expressed in gastrointestinal tract, female tissues, and lung. It is less expressed in muscle, skin, endocrine, male, and female tissues (http://www.proteinatlas.org).
Atlas Image
Figure 5. Expression profile of SLC6A4 in different tissues/organs in human. Data were taken from The Human Protein Atlas (http://www.proteinatlas.org) in December, 2018.

Localisation

SLC6A4 is found in various cellular compartments such as cytosol, endosome, plasma membrane, and integral component of plasma membrane, integral component of postsynaptic membrane, integral component of presynaptic membrane, endomembrane system, neuron projection, and serotonergic synapse (Müller et al., 2006; Brenner et al., 2007; Ahmed et al., 2008; Ahmed et al., 2009; Gaudet et al., 2011).

Function

5-HTT protein activity relies on the concentrations of intracellular potassium and extracellular sodium and chloride ions. It also depends on the membrane potential generated by sodium-potassium adenosine triphosphatase for the activity of the 5-HTT protein. The 5-HTT protein binds itself to sodium, serotonin and chloride ions, respectively. Thus, the membrane potential mediates the release of sodium and chloride molecules pre-bound to the 5-HTT protein and the 5-HTT protein passes into the cell. The 5-HTT protein releases serotonin in the cell and binds a potassium ion to itself. 5-HTT is activated by potassium ion and may be out of the cell. Serotonin (5-hydroxytryptamine; 5-HT) is an important neurotransmitter substance in the central and peripheral nervous system. After release of 5-HT into brain synapses, the Na+ and CI-ions-dependent high-affinity serotonin transporter SLC6A4 (also called 5-hydroxytryptamine transporter, 5-HTT, SERT), which is localized in presynaptic neuronal membranes, effectively clears 5-HT from the synaptic space. Thus, the synaptic activity of 5-HT is terminated by 5-HTT and reintroduced into the neurotransmitter pool for re-use. In this way, 5-HTT has an important role in the retrieval of serotonin and the execution of serotonergic function (Gelernter J. Et al., 1998, Catalano M., 1999).
The 5-HTT activity is rapidly regulated by a number of G-protein-linked receptors and protein kinase-associated pathways including protein kinase C (PKC), PRKG1 (protein kinase G, PKG), and p38 mitogen-activated protein kinase (MAPK). The PKC-dependent phosphorylation and down-regulation of the 5-HTT protein is sensitive to extracellular 5-HT and plays a regulatory role in the transport of 5-HT (Ramamoorthy et al., 1998; Ramamoorthy et al., 1999; Zhu et al., 2004; Samuvel et al., 2005; Prasad et al., 2005).
Atlas Image
Figure 6. Serotonergic Synapse Pathway Map. Once released from presynaptic axonal terminals, 5-HT binds to receptors, which have been divided into 7 subfamilies on the basis of conserved structures and signalling mechanisms. These families include the ionotropic 5-HT3 receptors and G-protein-coupled 5-HT receptors, the 5-HT1 (Gi /Go -coupled), 5-HT2 (Gq-coupled), 5-HT4/6/7 (Gs-coupled) and 5-HT5 receptors. Presynaptically localized 5-HT1B receptors are thought to be the autoreceptors that suppress excess 5-HT release. 5-HTs actions are terminated by transporter- mediated reuptake into neurons, leading to catabolism by monoamine oxidase. Data were taken from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in February, 2019.
Atlas Image
Figure 7. Pairwise alignment of SLC6A4 gene protein sequences (in distance from human) (HomoloGene, NCBI).

Mutations

Note

Most frequent mutations are located in the 5-HTTLPR of the promoter region of SLC6A4 gene. These mutations lead to the clinical picture of Autism (rs6365, rs28914832, rs140700) (Sutcliffe et al., 2005 ; Landaas et al., 2010 ; Adamsen et al., 2011), Increased rigid-compulsive behaviour in autism (rs28914833, rs28914834) (Sutcliffe et al., 2005; Rao et al., 2017), Obsessive-compulsive disorder (rs25532) (Wendland et al., 2007), Major depressive disorder (rs6354) (Rao et al., 2017), Panic disorder (rs3813034) (Gyawali et al., 2010), Unipolar disorder (Ogilvie et al., 1996), and Pulmonary arterial hypertension (Eddahibi et al., 2003) (Table 2).
Missense/Nonsense Mutations
#LocationMutationProteinReported PhenotypeReference
1Exon 2c.10A>Gp.T4AEnhanced 5-HT transport activityParasad et al., 2005
2Exon2c.167G>Cp.G56AAutism, association withSutcliffe et al., 2005
Camarena et al., 2012
3chr17:30218213  c.603G>Cp.K201NIncreased transporter activityRasmussen et al., 2009
4Exon 4c.643G>Ap.E215KMAPK nonresponsivenessParasad et al., 2005
5Exon 6c.878C>Tp.S293FEnhanced 5-HT transport activityParasad et al., 2005
6Exon 7c.1016C>Tp.P339LReduced uptake activityParasad et al., 2005
7Exon 8c.1084C>Ap.L362MEnhanced 5-HT transport activityParasad et al.i 2005
8Exon 9c.1273A>Cp.I425LAutism, association withSutcliffe et al., 2005
9Exon 9c.1273A>Gp.I425VObsessive-compulsive disorder,susceptibility, associationOzaki et al., 2003
Moya et al., 2013
10Exon 10c.1393T>Cp.F465LIncreased rigid-compulsive behavior in autism, association with  Sutcliffe et al., 2005
11Exon 12c.1648C>Gp.L550VIncreased rigid-compulsive behavior in autism, association withSutcliffe et al., 2005
Rao et al., 2017
12Exon13c.1815A>Cp.K605NMAPK nonresponsivenessParasad et al., 2005
Rao et al., 2017
13Exon 14c.1861C>Tp.P621SMAPK nonresponsivenessParasad et al., 2005
Splicing Mutation
14chr17:30216371c.838-155G>ANAAutism, association withSutcliffe et al., 2005
Landaas et al., 2010
Regulatory Mutation
15chr17:30237328c.-1936G>ANAObsessive-compulsive disorder, association withHu et al., 2006
Perroud et al., 2010
Hung et al., 2011
Moya et al., 2013
Stacey et al., 2013
16chr17:30237152c.-1760T>CNAObsessive-compulsive disorder, association withWendland et al., 2008
Fuxman Bass et al., 2015
17chr17:30222880c.-185A>CNAMajor depressive disorder, association withRao et al., 2017
18chr17:30197993c.463T>GNAIncreased expressionVallender et al., 2008
Seneviratne et al., 2009
19chr17:30197786c.670T>GNaPanic disorder, association withGyawali et al., 2010
Aoki et al., 2010
Hartley et al., 2012
Deletion
20Promoterc.1212-1255 del TGCAGCCNAAnxiety related traits, association withHelis et al., 1996
Marziniak et al., 2005
Borroni et al., 2006
Albani et al., 2009
 LocationRepetition SequenceNumber Of Repetitions  Reported Disease/PhenotypeReferance
21Intron 2(GGCTGYGACCYRGRRTG)n  10-12Unipolar disorder, association withOgilvie et al., 1996
22Intron 2(GGCTGYGACCYRGRRTG)n12Pulmonary arterial hypertension, association withAllen et al., 2008: 
Cao et al., 2009

Table 2. Solute Carrier Family 6 Member 4 (SLC6A4) related mutations.

Implicated in

Top note
The serotonin carrier protein encoded by SLC6A4 gene is the target of serotonin selective reuptake inhibitors, an important class of antidepressant drugs (Ramoz et al., 2006). Three alleles of 17-bp VNTR (variable number tandem repeat) were detected in the intron 2 region of the gene, between 9 (Stin2.9), 10 (Stin2.10), and 12 (Stin2.12) copies. Presence of Stin2.9 allele in humans has been reported to increase the risk of Major depressive disorder (MDD) (Ogilvie et al., 1996). The 5-HTTLPR promoter sequence of the gene comprises two variant repeat length polymorphisms, known as the 16-element long (L) and 44-bp short (S) variant with 14 repetitive elements (Esterling et al., 1998; Sen et al., 2004). The L/L genotype from the 5-HTTLPR promoter variants causes more 5-HTT protein expression than the L/S or S/S variants (Canli and Lesch, 2007). Analysis of lymphoblastoid cell lines with different genotypes revealed that the basal activity of the L variant of the SLC6A4 gene promoter was two times greater than that of the S variant (Lesch et al., 1996). In a later study, the expression of the native SLC6A4 gene in cultured lymphoblast cell lines from subjects with different SLC6A4 promoter genotypes was examined (Lesch et al., 1996).The mRNA concentration of the SLC6A4 gene in L/L cells was found to be 1.4 to 1.7-fold higher than the L/S and S/S cells (Lesch et al., 1996). Bradley et al. (2005) directly measured serotonin transporter mRNA levels and also identified 4 loci containing the serotonin transporter gene from 85 independent lymphoblast lines. They found strong impact of 5-HTTLPR on the mRNA exression (Bradley et al., 2005).
The Gly56Ala substitution in the exon 2 of the SLC6A4 gene has been reported to be associated with autism and exhibit structurally high SERT activity (Sutcliffe et al., 2005). I425V substitution in the exon 9 of the SLC6A4 gene has been reported to be associated with obsessive-compulsive disorder (OCD) (Ozaki et al., 2003; Kilic et al., 2003; Zhang et al., 2007). In addition, A-1438G and T102C polymorphisms were reported to be associated with OCD (Taylor, 2013; Taylor, 2016). Rao et al. (2017) reported that I550V (exon 12) and K605N (exon 13) substitutions of the SLC6A4 gene are associated with major depression disorder (MDD) and SA (non-fatal suicidal behavior) in addition to autism and OCD in 36 Chinese patients.
Animal Experiments
When 5-HTT was temporarily inhibited by fluoxetine (selective serotonin re-uptake inhibitor) in the early developmental period of mice, it was observed that adult mice exhibited abnormal emotional behaviors. It has been reported that serotonin plays a critical role in the maturation of brain systems that regulate emotional function, and that the low expression level of the SLC6A4 gene may be related to the development of psychiatric disorders in adults (Ansorge et al., 2004). A study of transgenic mice overexpressing the SLC6A4 gene and wild-type mice showed that right ventricular pressure was 3-fold higher in transgenic mice (Maclean et al., 2004). Page et al. (2009) reported macrocephaly in Pten +/- mice. Female Pten +/- mice had socialization disorder, whereas male Pten +/- mice had no socialization disorder. This phenotype was exacerbated in mice with Pten and SLC6A4 double haploinsufficiency. As a result of these findings PTEN and SLC6A4 genes have been reported to be associated with autism spectrum disorder (ASD).
Entity name
Breast cancer
Note
High expression is found in breast cancer, but the gene product is not prognostic according to The Human Protein Atlas.
A fusion gene PIP4K2B /SLC6A4 was found in breast cancer (Yoshida et al., 2013).
Entity name
Obsessive-Compulsive Disorder (OCD)
Note
Hu et al. (2006) found that the gain-of-function homozygous L(A)L(A) genotype was 2-fold in patients with OCD compared to healthy individuals. In a replication study in 175 trios consisting of probands with OCD and their parents, the L(A) allele was 2-fold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerted 1.8-fold effect on risk of OCD, thus establishing the role of the HTT gene in OCD. In another study, the frequency of Stin2.12 allele in Asian patients with anxiety disorder (including OCD) was reported to be significantly higher compared to the healthy individuals (Ohara et al., 1998). There is also a possible association between OCD and Stin2.12 allele in Spanish Caucasian population (Baca-Garcia et al., 2007; Saiz et al., 2008).
Entity name
Anxiety-Related Personality Traits
Note
The homozygous or heterozygous form of the S-variant of the 5-HTTLPR polymorphism in the SLC6A4 gene has been reported to be associated with lower expression and openness, and higher neuroticism (Lesch et al., 1996). Individuals with 1-2 copies of the S-variant of the 5-HTTLPR polymorphism, which is implicated in reduced 5-HTT expression and function and increased fear and anxiety-related behaviours, demonstrated higher amygdala activity in response to fearful stimuli compared with individuals homozygous for the L-variant (Hariri et al., 2002). The altered function of the serotonin neurotransmission system causes aggressive behaviour in Alzheimers patients (AD) (Brown et al., 1982; Palmer et al., 1988). In a study conducted on 137 AD patients, the aggressive behaviours (58 patients) were associated with L/L genotype (Sukonick et al., 2001).
Entity name
Major Depressive Disorder (MDD)
Note
People with L/S or S/S allele in stressful life conditions have been reported to have more depression and suicidal tendency than those with L/L allele (Caspi et al., 2003). They also reported that the individuals response to environmental insults was determined by environmental-gene interaction (Caspi et al., 2003). In a study conducted on Pomerania population, the relationship of S-variant with environmental interaction and depression was determined. The results of the study supported previous studies on the gene-environment interaction of the S allele. It has also been revealed to cause high mental vulnerability to social stress and chronic diseases (Grabe et al., 2005). Homozygous or heterozygous genotypes of the S-variant were associated with stress-related depression and anxiety disorders in elite athletes (Petito et al., 2016). The 5-HTTLPR polymorphisms of the SLC6A4 gene have been reported to be associated with prenatal and postnatal depression (Sanjuan et al., 2008; Oberlander et al., 2013). Interestingly, the genetic and epigenetic variations have been reported in the SLC6A4 gene of children exposed to prenatal depression (Devlin et al., 2010; Oppenheimer et al., 2013; Wankerl et al., 2014; Babineau et al., 2014; Green et al., 2017). 5-HTTLPR polymorphisms and DNA methylations of SLC6A4 gene have been reported to be associated with depression (Devlin et al., 2010; Sugawara et al., 2013).
Entity name
Seasonal Affective Disorder (SAD)
Note
Willeit et al. (2003) genotyped 284 subjects (138 SAD patients and 146 healthy individuals) to examine the relationship between L and S-variants in the 5-HTTLPR polymorphism of SLC6A4 gene with SAD. The distribution of genotype and S allele frequency was found similar between patients and healthy subjects, while they were correlated with the subtypes of DSM-IV depression. L allele was correlated with melancholic depression whereas S allele was related to atypical depression. It was concluded that 5-HTTLPR polymorphism affects the phenotypic disease expression but it is not the cause of disease.
The effects of light therapy on serotonin transporter binding (5-HTT BPND), which is biomarker of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter was studied. In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC with respect to placebo, whereas in the fall, no significant change in 5-HTT BPND was measured. In this context, it has been reported that 5-HTT BPND can be used as a biomarker for the assessment of the modification effects of light therapy (Harrison et al., 2015). In a study on 20 SAD patients and 20 healthy participants the impact of seasonal (winter and summer) variations on 5-HTT activity was investigated by analysing brain 5-HTT BPND levels. The study reported a significant increase in 5-HTT BPND in different brain regions (including ACC and PFC) especially in severe SAD during winter. The 5-HTT BPND as biomarker in the diagnosis of SAD is important as it can be applied for the development of prevention strategies against disease progress (Tyrer et al., 2016).
Entity name
Alcoholism
Note
A meta-analysis study (data from 3,489 alcoholics and 2,325 controls) was conducted on the association of 5-HTTLPR polymorphisms of SLC6A4 with alcohol dependence. It has been reported that alcohol dependence complicated by a comorbid psychiatric condition or a more severe form of alcoholism is associated with the S-variant (Feinn et al., 2005). In a study conducted on university students, the S-variant was reported to be associated with high alcohol consumption (Herman et al., 2003). High alcohol consumption in men with homozygous or heterozygote genotypes of the S-variant has been reported, whereas it was seen only in the heterozygous women (Munaf et al., 2005). In a study conducted on 273 (78.5% male) alcoholic individuals of the Caucasus and Hispanic origin, it was reported that G allele carriers for the rs1042173 SNP in the 3UTR region of the SLC6A4 gene had lower alcohol consumption than T-allele homozygotes (Seneviratne et al., 2009). G allele transfection to HeLa cells resulted in higher mRNA and protein expression compared to T allele transfected cells (Seneviratne et al., 2009).
Entity name
Sudden Infant Death Syndrome (SIDS)
Note
L/L genotype and excess of L-variant have been reported to be associated with SIDS (Narita et al., 2001; Weese-Mayer et al., 2003). In addition, the Stin2.12 allele has been associated with SIDS in African-Americans and Japanese, whereas it is not associated with SIDS in Caucasian-Americans (Narita et al., 2001; Weese-Mayer et al., 2003).
Entity name
Panic Disorder (PD)
Note
The rs3813034 variant in the 3UTR region of the SLC6A4 gene has been reported to be related to PD (Gyawali et al., 2010). Decreased SLC6A4 gene expression due to the gene polymorphisms in midbrain, hypothalamus and temporal lobe has been associated with PD (Maron et al., 2006). Strug et al. (2010) reported that rs140701 variant of the SLC6A4 gene may be associated with PD.
Entity name
Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness (MDI)
Note
The disorder of the neurotransmitter system, including serotonin and monoamines, has been reported to be associated with bipolar disorder (Scott et al., 1979; Kapur and Remington, 1992). The patients with BPAD without panic disorder exhibited statistically higher frequencies of the Catechol O-Methyltransferase (COMT) Met158 and the S-variant 5-HTTLPR genotypes with respect to healthy individuals (Rotondo et al., 2002). When the relationship between L and S-variant polymorphisms of SLC6A4 gene and BPAD and unipolar depression were investigated by meta-analysis study, it was revealed that the S-variant could be associated with BPAD but not with unipolar depression. The L-variant was not implicated in BPAD and/or unipolar depression (Lasky-Su et al., 2005). However other studies reported no significant relationship between SLC6A4 5-HTTLPR and VNTR polymorphisms and BPAD (Mendlewicz et al., 2004; Cho et al., 2005). The association between epigenetic variations of SLC6A4 gene and BPAD were studied on 20 bipolar monozygotic twins with respect to 20 healthy subjects. The promoter-wide DNA methylation analysis of lymphoblastic cell lines (LCLs) revealed DNA hypermethylation in SLC6A4 gene that can be an epigenetic mark resulting from a G×E interaction leading to the development of BPED (Sugawara et al., 2011). In a study on the association of SLC6A4 and DRD2 (dopamine D2 receptor) genes with BPED, the gender specific differences in SLC6A4 gene polymorphisms were reported. The results revealed gender-specific association of the DRD2 A1/A1 and the 5-HTTLPR S/S, S/LG, and LG/LG (S+) genotypes in type I and type II men, but not in women. A significant interaction for the DRD2 A1/A1 and 5-HTTLPR S+ polymorphisms was also found only in type I and type II men (Wang et al., 2014).
Entity name
Pulmonary Hypertension (PPH)
Note
Smooth muscle cells (SMC) of pulmonary artery in PPH patients grow faster than controls when 5-HTT expression is stimulated by serotonin. As a result of these findings, 5-HTT has been shown to play a key role in the pathogenesis of SMC proliferation and 5-HTT polymorphisms are associated with PHH (Eddahibi et al., 2001). The higher 5-HTT expression was reported in pulmonary artery SMC in patients with L/L genotypes compared to L/S and S/S genotypes, resulting in more severe PPH. (Eddahibi et al., 2003). In a study on the association of idiopathic PPH with 5-HTT polymorphism in children, the L/L genotype has been reported to be associated with the aetiology of PPH (Vachharajani and Saunders, 2005).

Article Bibliography

Pubmed IDLast YearTitleAuthors
211833712011Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.Adamsen D et al
192707312009The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network.Ahmed BA et al
182270692008Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter.Ahmed BA et al
195210892009Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy.Albani D et al
185839792008Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.Allen NC et al
155141602004Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.Ansorge MS et al
203032732010The association between personality, pain threshold and a single nucleotide polymorphism (rs3813034) in the 3'-untranslated region of the serotonin transporter gene (SLC6A4).Aoki J et al
248279222015Prenatal depression and 5-HTTLPR interact to predict dysregulation from 3 to 36 months--a differential susceptibility model.Babineau V et al
171740182007Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene.Baca-Garcia E et al
165820432006Cumulative effect of COMT and 5-HTTLPR polymorphisms and their interaction with disease severity and comorbidities on the risk of psychosis in Alzheimer disease.Borroni B et al
158588222005Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription.Bradley SL et al
175068582007Plasma serotonin levels and the platelet serotonin transporter.Brenner B et al
61772561982Aggression, suicide, and serotonin: relationships to CSF amine metabolites.Brown GL et al
226220722012SLC6A4 rare variant associated with eating disorders in Mexican patients.Camarena B et al
177264762007Long story short: the serotonin transporter in emotion regulation and social cognition.Canli T et al
198868582009Association study of serotonin transporter gene polymorphisms and ventricular septal defects related possible pulmonary arterial hypertension in Chinese population.Cao H et al
128697662003Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.Caspi A et al
104415661999The challenges of psychopharmacogenetics.Catalano M et al
127199812004Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.Chen NH et al
158247452005Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis.Cho HJ et al
208089442010Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.Devlin AM et al
116026212001Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.Eddahibi S et al
95145851998Serotonin transporter (5-HTT) gene and bipolar affective disorder.Esterling LE et al
156356382005Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.Feinn R et al
259102132015Human gene-centered transcription factor networks for enhancers and disease variants.Fuxman Bass JI et al
218736352011Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.Gaudet P et al
97667631998Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects.Gelernter J et al
152639052005Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden.Grabe HJ et al
274271782017Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months.Green CG et al
199692872010Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder.Gyawali S et al
121307842002Serotonin transporter genetic variation and the response of the human amygdala.Hariri AR et al
258914842015Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex.Harrison SJ et al
224316342012Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory.Hartley CA et al
86321901996Allelic variation of human serotonin transporter gene expression.Heils A et al
129155252003Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population.Herman AI et al
166424372006Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.Hu XZ et al
219643902011Association between suicide attempt and a tri-allelic functional polymorphism in serotonin transporter gene promoter in Chinese patients with schizophrenia.Hung CF et al
85993931996Serotonin-dopamine interaction and its relevance to schizophrenia.Kapur S et al
128696492003A human serotonin transporter mutation causes constitutive activation of transport activity.Kilic F et al
201133572010An international multicenter association study of the serotonin transporter gene in persistent ADHD.Landaas ET et al
155786062005Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders.Lasky-Su JA et al
89294131996Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.Lesch KP et al
219512702012Association study of functional polymorphisms in serotonin transporter gene with temporal lobe epilepsy in Han Chinese population.Li J et al
150240132004The role of N-glycosylation in function and surface trafficking of the human dopamine transporter.Li LB et al
168706142006Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2.Müller HK et al
106113711999A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo.MacKenzie A et al
150787992004Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension.MacLean MR et al
271112302016Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.Margolis KG et al
161320632006Serotonin function in panic disorder: important, but why?Maron E et al
156429262005A functional serotonin transporter gene polymorphism is associated with migraine with aura.Marziniak M et al
87001331996Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition.Melikian HE et al
147351612004Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.Mendlewicz J et al
164730132006N-linked oligosaccharides as outfitters for glycoprotein folding, form and function.Mitra N et al
236301622013Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.Moya PR et al
157297462005Association between the serotonin transporter gene and alcohol consumption in social drinkers.Munafò MR et al
188240002008How 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.Murphy DL et al
113357452001Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population.Narita N et al
204397952010Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age.Oberlander TF et al
86020041996Polymorphism in serotonin transporter gene associated with susceptibility to major depression.Ogilvie AD et al
97878781998Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders.Ohara K et al
77218691995The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter.Olivares L et al
233491062013Youth genetic vulnerability to maternal depressive symptoms: 5-HTTLPR as moderator of intergenerational transmission effects in a multiwave prospective study.Oppenheimer CW et al
145934312003Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.Ozaki N et al
192088142009Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.Page DT et al
24573531988Possible neurotransmitter basis of behavioral changes in Alzheimer's disease.Palmer AM et al
208626972010Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder.Perroud N et al
272579422016The Relationship between Personality Traits, the 5HTT Polymorphisms, and the Occurrence of Anxiety and Depressive Symptoms in Elite Athletes.Petito A et al
189573752009Enhanced activity of human serotonin transporter variants associated with autism.Prasad HC et al
160555632005Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase.Prasad HC et al
104270041999Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.Ramamoorthy S et al
166167192006Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism.Ramoz N et al
279649442017Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.Rao S et al
195006022009A single nucleotide polymorphism in the human serotonin transporter introduces a new site for N-linked glycosylation.Rasmussen TN et al
117726852002Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder.Rotondo A et al
156347642005A role for p38 mitogen-activated protein kinase in the regulation of the serotonin transporter: evidence for distinct cellular mechanisms involved in transporter surface expression.Samuvel DJ et al
189783182008Mood changes after delivery: role of the serotonin transporter gene.Sanjuan J et al
1546821979Studies on human blood platelets in affective disorder.Scott M et al
151081872004Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.Sen S et al
190325742009Characterization of a functional polymorphism in the 3' UTR of SLC6A4 and its association with drinking intensity.Seneviratne C et al
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Other Information

Locus ID:

NCBI: 6532
MIM: 182138
HGNC: 11050
Ensembl: ENSG00000108576

Variants:

dbSNP: 6532
ClinVar: 6532
TCGA: ENSG00000108576
COSMIC: SLC6A4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000108576ENST00000261707P31645
ENSG00000108576ENST00000394821J3KPR9
ENSG00000108576ENST00000401766P31645
ENSG00000108576ENST00000579221J3QKP3
ENSG00000108576ENST00000650711P31645

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

PathwaySourceExternal ID
Serotonergic synapseKEGGhsa04726
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Clearance In The Synaptic CleftREACTOMER-HSA-112311
Serotonin clearance from the synaptic cleftREACTOMER-HSA-380615

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10074escitalopramChemicalClinicalAnnotation, VariantAnnotationambiguousPD19272758, 19567893, 20212518, 23095326, 24014145
PA124CYP2C19GeneDataAnnotationassociated
PA128CYP2D6GeneDataAnnotationassociated
PA128406954Weight gainDiseaseVariantAnnotationassociatedPD
PA164713257Selective serotonin reuptake inhibitorsChemicalClinicalAnnotation, Literature, MultilinkAnnotation, VariantAnnotationassociatedPD17414739, 19204908, 22086748, 24930681, 28639488
PA164784024peginterferon alfa-2bChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA165860788evodiamineChemicalVariantAnnotationassociatedPK21647174
PA165860812berberineChemicalVariantAnnotationassociatedPK21647174
PA166048714PregnancyDiseaseVariantAnnotationassociatedPD28639488
PA193HTR2AGeneDataAnnotationassociated
PA27093CYP1A2GeneDataAnnotationassociated
PA443309AlcoholismDiseaseClinicalAnnotation, VariantAnnotationassociatedPD21247998, 31595439
PA443853DementiaDiseaseVariantAnnotationassociatedPD
PA443928DizzinessDiseaseVariantAnnotationassociatedPD23859574
PA443937Drug ToxicityDiseaseClinicalAnnotationassociatedPD20031235, 23859574
PA444367Heart Defects, CongenitalDiseaseVariantAnnotationassociatedPD28639488
PA444624Sleep Initiation and Maintenance DisordersDiseaseVariantAnnotationassociatedPD14573314
PA445043Opioid-Related DisordersDiseaseClinicalAnnotation, VariantAnnotationassociatedPD29333880
PA445048NauseaDiseaseVariantAnnotationnot associatedPD12208565, 17697394
PA445208PainDiseaseClinicalAnnotationassociatedPD32432768
PA445452Psychomotor AgitationDiseaseVariantAnnotationassociatedPD14573314
PA445876Tobacco Use DisorderDiseaseClinicalAnnotationassociatedPD21658141
PA446863Hepatitis C, ChronicDiseaseClinicalAnnotation, VariantAnnotationassociatedPD
PA447197Attention Deficit Disorder with HyperactivityDiseaseVariantAnnotationnot associatedPD17948872
PA447207Depressive DisorderDiseaseClinicalAnnotation, VariantAnnotationambiguousPD11543734, 16515395, 17697394, 19272758, 19451862, 19567893, 20212518, 23510446, 24014145
PA447209Mood DisordersDiseaseClinicalAnnotation, VariantAnnotationambiguousPD10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16874005, 17146470, 17853254, 17914325, 18983505, 18987562, 19606452, 19800133, 23288236
PA447211Obsessive-Compulsive DisorderDiseaseVariantAnnotationnot associatedPD12082589
PA447212Panic DisorderDiseaseVariantAnnotationambiguousPD16034444, 16822601, 19259652, 19800133, 21688171
PA447216SchizophreniaDiseaseVariantAnnotationassociatedPD20031235, 20452607
PA447278DepressionDiseaseClinicalAnnotation, DataAnnotation, VariantAnnotationambiguousPD10683861, 12374640, 16302021, 17018806, 18253134, 19272758, 19567893, 20212518, 24014145
PA447321Depressive Disorder, MajorDiseaseClinicalAnnotation, DataAnnotation, VariantAnnotationambiguousPKPD10653220, 10683861, 11027924, 11543734, 11817517, 12082589, 12208565, 12476327, 12955294, 14573314, 14624186, 15274037, 15520364, 15812265, 15993855, 16302021, 16580768, 16874005, 17018806, 17414739, 17606812, 17853254, 17914325, 18253134, 18452396, 18987562, 19272758, 19468717, 19567893, 19606452, 19800133, 19825907, 20584552, 20640435, 21962566, 22885912, 23095326, 23288236, 23510446, 24014145, 27439447, 9857976
PA448073ethanolChemicalClinicalAnnotationassociatedPD31595439
PA448685buprenorphineChemicalClinicalAnnotation, VariantAnnotationassociatedPD29333880
PA448687bupropionChemicalClinicalAnnotationassociatedPD21658141
PA449015citalopramChemicalClinicalAnnotation, Pathway, VariantAnnotationambiguousPD14624186, 17606812, 18618621, 19468717, 19741567, 19996755, 20640435, 23510446, 23973251
PA449048clomipramineChemicalClinicalAnnotation, VariantAnnotationassociatedPD10867985
PA449061clozapineChemicalVariantAnnotationassociatedPD20452607
PA449673fluoxetineChemicalClinicalAnnotation, Pathway, VariantAnnotationambiguousPD10683861, 12476327, 14573314, 15993855, 16302021, 17018806, 19468717, 19741567, 20584552, 20640435, 22885912, 27439447
PA449690fluvoxamineChemicalClinicalAnnotation, Pathway, VariantAnnotationambiguousPD11543734, 11817517, 12082589, 12208565, 12374640, 15274037, 15812265, 16874005, 19741567, 23288236, 9857976
PA449841haloperidolChemicalMultilinkAnnotation, VariantAnnotationassociatedPD20031235, 27023437
PA450401methadoneChemicalClinicalAnnotation, VariantAnnotationassociatedPD29333880
PA450464methylphenidateChemicalVariantAnnotationnot associatedPD17948872
PA450522mirtazapineChemicalClinicalAnnotation, VariantAnnotationambiguousPD15520364
PA450550morphineChemicalClinicalAnnotationassociatedPD32432768
PA450657nortriptylineChemicalVariantAnnotationnot associatedPD11027924, 19567893
PA450688olanzapineChemicalClinicalAnnotation, VariantAnnotationassociatedPD20031235, 23859574
PA450705ondansetronChemicalClinicalAnnotation, VariantAnnotationassociatedPD21247998
PA450801paroxetineChemicalClinicalAnnotation, Pathway, VariantAnnotationambiguousPD10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16034444, 16822601, 16874005, 17697394, 17853254, 17914325, 18983505, 18987562, 19259652, 19468717, 19606452, 19741567, 19800133, 20640435, 21688171, 23288236
PA450966pindololChemicalVariantAnnotationnot associatedPD9857976
PA451201quetiapineChemicalClinicalAnnotation, VariantAnnotationassociatedPD20031235, 23859574
PA451241ribavirinChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA451257risperidoneChemicalClinicalAnnotation, VariantAnnotationassociatedPD20031235, 23859574
PA451333sertralineChemicalClinicalAnnotation, Pathway, VariantAnnotationambiguousPKPD12955294, 16580768, 17018806, 18452396, 19741567, 19800133, 19825907, 21962566, 22885912
PA451866venlafaxineChemicalVariantAnnotationnot associatedPD19468717, 24014145
PA452229antidepressantsChemicalClinicalAnnotation, VariantAnnotationambiguousPD16515395, 17146470, 18253134, 19451862
PA452233antipsychoticsChemicalVariantAnnotationassociatedPD20031235

References

Pubmed IDYearTitleCitations
370703942024Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.1
381034522024DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.0
382883882024Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation.0
383613162024SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health.1
384658222024[The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression].0
387537622024PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs.0
389283722024Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses.0
370703942024Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.1
381034522024DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.0
382883882024Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation.0
383613162024SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health.1
384658222024[The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression].0
387537622024PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs.0
389283722024Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses.0
366492602023Unravelling neurotransmitters impairment in primary progressive aphasias.3

Citation

Rafig Gurbanov ; Berkay Kalkanci

SLC6A4 (solute carrier family 6 member 4)

Atlas Genet Cytogenet Oncol Haematol. 2019-03-01

Online version: http://atlasgeneticsoncology.org/gene/49951/gene-explorer/css/lib/hgnc