SLC6A4 (solute carrier family 6 member 4)

2019-03-01 Rafig Gurbanov , Berkay Kalkanci Affiliation

Identity

HGNC

SLC6A4

LOCATION

17q11.2

IMAGE

LEGEND

Figure 1. Genomic location of SLC6A4 (Chromosome 17 - NC_000017.11 Reference GRCh38.p12 Primary Assembly)

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

6532

ALIAS

5-HTT,5-HTTLPR,5HTT,HTT,OCD1,SERT,SERT1,hSERT

FUSION GENES

Show Gene Fusions

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).

Figure 3. Numbers and illustrative sizes of exons of human SLC6A4. (https:\\www.atlasgeneticsoncology.org)

Transcription

The gene has 5 transcripts (Table 1)

Name	Transcript ID	bp	Protein (aa)	Biotype
SLC6A4-201	ENST00000261707.7	6604	630 aa	Protein coding
SLC6A4-202	ENST00000394821.2	2160	618 aa	Protein coding
SLC6A4-203	ENST00000401766.6	6543	630 aa	Protein coding
SLC6A4-204	ENST00000578609.1	566	No protein	Retained intron
SLC6A4-205	ENST00000579221.5	1069	72 aa	Nonsense 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).

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).

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).

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.

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
#	Location	Mutation	Protein	Reported Phenotype	Reference
1	Exon 2	c.10A>G	p.T4A	Enhanced 5-HT transport activity	Parasad et al., 2005
2	Exon2	c.167G>C	p.G56A	Autism, association with	Sutcliffe et al., 2005
					Camarena et al., 2012
3	chr17:30218213	c.603G>C	p.K201N	Increased transporter activity	Rasmussen et al., 2009
4	Exon 4	c.643G>A	p.E215K	MAPK nonresponsiveness	Parasad et al., 2005
5	Exon 6	c.878C>T	p.S293F	Enhanced 5-HT transport activity	Parasad et al., 2005
6	Exon 7	c.1016C>T	p.P339L	Reduced uptake activity	Parasad et al., 2005
7	Exon 8	c.1084C>A	p.L362M	Enhanced 5-HT transport activity	Parasad et al.i 2005
8	Exon 9	c.1273A>C	p.I425L	Autism, association with	Sutcliffe et al., 2005
9	Exon 9	c.1273A>G	p.I425V	Obsessive-compulsive disorder,susceptibility, association	Ozaki et al., 2003
					Moya et al., 2013
10	Exon 10	c.1393T>C	p.F465L	Increased rigid-compulsive behavior in autism, association with	Sutcliffe et al., 2005
11	Exon 12	c.1648C>G	p.L550V	Increased rigid-compulsive behavior in autism, association with	Sutcliffe et al., 2005
					Rao et al., 2017
12	Exon13	c.1815A>C	p.K605N	MAPK nonresponsiveness	Parasad et al., 2005
					Rao et al., 2017
13	Exon 14	c.1861C>T	p.P621S	MAPK nonresponsiveness	Parasad et al., 2005
Splicing Mutation
14	chr17:30216371	c.838-155G>A	NA	Autism, association with	Sutcliffe et al., 2005
					Landaas et al., 2010
Regulatory Mutation
15	chr17:30237328	c.-1936G>A	NA	Obsessive-compulsive disorder, association with	Hu et al., 2006
					Perroud et al., 2010
					Hung et al., 2011
					Moya et al., 2013
					Stacey et al., 2013
16	chr17:30237152	c.-1760T>C	NA	Obsessive-compulsive disorder, association with	Wendland et al., 2008
					Fuxman Bass et al., 2015
17	chr17:30222880	c.-185A>C	NA	Major depressive disorder, association with	Rao et al., 2017
18	chr17:30197993	c.463T>G	NA	Increased expression	Vallender et al., 2008
					Seneviratne et al., 2009
19	chr17:30197786	c.670T>G	Na	Panic disorder, association with	Gyawali et al., 2010
					Aoki et al., 2010
					Hartley et al., 2012
Deletion
20	Promoter	c.1212-1255 del TGCAGCC	NA	Anxiety related traits, association with	Helis et al., 1996
					Marziniak et al., 2005
					Borroni et al., 2006
					Albani et al., 2009
	Location	Repetition Sequence	Number Of Repetitions	Reported Disease/Phenotype	Referance

21	Intron 2	(GGCTGYGACCYRGRRTG)n	10-12	Unipolar disorder, association with	Ogilvie et al., 1996
22	Intron 2	(GGCTGYGACCYRGRRTG)n	12	Pulmonary arterial hypertension, association with	Allen 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 ID	Last Year	Title	Authors
21183371	2011	Autism 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
19270731	2009	The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network.	Ahmed BA et al
18227069	2008	Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter.	Ahmed BA et al
19521089	2009	Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy.	Albani D et al
18583979	2008	Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.	Allen NC et al
15514160	2004	Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.	Ansorge MS et al
20303273	2010	The 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
24827922	2015	Prenatal depression and 5-HTTLPR interact to predict dysregulation from 3 to 36 months--a differential susceptibility model.	Babineau V et al
17174018	2007	Association 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
16582043	2006	Cumulative 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
15858822	2005	Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription.	Bradley SL et al
17506858	2007	Plasma serotonin levels and the platelet serotonin transporter.	Brenner B et al
6177256	1982	Aggression, suicide, and serotonin: relationships to CSF amine metabolites.	Brown GL et al
22622072	2012	SLC6A4 rare variant associated with eating disorders in Mexican patients.	Camarena B et al
17726476	2007	Long story short: the serotonin transporter in emotion regulation and social cognition.	Canli T et al
19886858	2009	Association study of serotonin transporter gene polymorphisms and ventricular septal defects related possible pulmonary arterial hypertension in Chinese population.	Cao H et al
12869766	2003	Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.	Caspi A et al
10441566	1999	The challenges of psychopharmacogenetics.	Catalano M et al
12719981	2004	Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.	Chen NH et al
15824745	2005	Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis.	Cho HJ et al
20808944	2010	Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.	Devlin AM et al
11602621	2001	Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.	Eddahibi S et al
9514585	1998	Serotonin transporter (5-HTT) gene and bipolar affective disorder.	Esterling LE et al
15635638	2005	Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.	Feinn R et al
25910213	2015	Human gene-centered transcription factor networks for enhancers and disease variants.	Fuxman Bass JI et al
21873635	2011	Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.	Gaudet P et al
9766763	1998	Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects.	Gelernter J et al
15263905	2005	Mental 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
27427178	2017	Prenatal 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
19969287	2010	Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder.	Gyawali S et al
12130784	2002	Serotonin transporter genetic variation and the response of the human amygdala.	Hariri AR et al
25891484	2015	Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex.	Harrison SJ et al
22431634	2012	Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory.	Hartley CA et al
8632190	1996	Allelic variation of human serotonin transporter gene expression.	Heils A et al
12915525	2003	Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population.	Herman AI et al
16642437	2006	Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.	Hu XZ et al
21964390	2011	Association between suicide attempt and a tri-allelic functional polymorphism in serotonin transporter gene promoter in Chinese patients with schizophrenia.	Hung CF et al
8599393	1996	Serotonin-dopamine interaction and its relevance to schizophrenia.	Kapur S et al
12869649	2003	A human serotonin transporter mutation causes constitutive activation of transport activity.	Kilic F et al
20113357	2010	An international multicenter association study of the serotonin transporter gene in persistent ADHD.	Landaas ET et al
15578606	2005	Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders.	Lasky-Su JA et al
8929413	1996	Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.	Lesch KP et al
21951270	2012	Association study of functional polymorphisms in serotonin transporter gene with temporal lobe epilepsy in Han Chinese population.	Li J et al
15024013	2004	The role of N-glycosylation in function and surface trafficking of the human dopamine transporter.	Li LB et al
16870614	2006	Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2.	Müller HK et al
10611371	1999	A 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
15078799	2004	Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension.	MacLean MR et al
27111230	2016	Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.	Margolis KG et al
16132063	2006	Serotonin function in panic disorder: important, but why?	Maron E et al
15642926	2005	A functional serotonin transporter gene polymorphism is associated with migraine with aura.	Marziniak M et al
8700133	1996	Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition.	Melikian HE et al
14735161	2004	Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.	Mendlewicz J et al
16473013	2006	N-linked oligosaccharides as outfitters for glycoprotein folding, form and function.	Mitra N et al
23630162	2013	Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder.	Moya PR et al
15729746	2005	Association between the serotonin transporter gene and alcohol consumption in social drinkers.	Munafò MR et al
18824000	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.	Murphy DL et al
11335745	2001	Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population.	Narita N et al
20439795	2010	Prenatal 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
8602004	1996	Polymorphism in serotonin transporter gene associated with susceptibility to major depression.	Ogilvie AD et al
9787878	1998	Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders.	Ohara K et al
7721869	1995	The role of N-glycosylation in the targeting and activity of the GLYT1 glycine transporter.	Olivares L et al
23349106	2013	Youth genetic vulnerability to maternal depressive symptoms: 5-HTTLPR as moderator of intergenerational transmission effects in a multiwave prospective study.	Oppenheimer CW et al
14593431	2003	Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.	Ozaki N et al
19208814	2009	Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior.	Page DT et al
2457353	1988	Possible neurotransmitter basis of behavioral changes in Alzheimer's disease.	Palmer AM et al
20862697	2010	Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder.	Perroud N et al
27257942	2016	The Relationship between Personality Traits, the 5HTT Polymorphisms, and the Occurrence of Anxiety and Depressive Symptoms in Elite Athletes.	Petito A et al
18957375	2009	Enhanced activity of human serotonin transporter variants associated with autism.	Prasad HC et al
16055563	2005	Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase.	Prasad HC et al
10427004	1999	Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.	Ramamoorthy S et al
16616719	2006	Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism.	Ramoz N et al
27964944	2017	Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.	Rao S et al
19500602	2009	A single nucleotide polymorphism in the human serotonin transporter introduces a new site for N-linked glycosylation.	Rasmussen TN et al
11772685	2002	Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder.	Rotondo A et al
15634764	2005	A 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
18978318	2008	Mood changes after delivery: role of the serotonin transporter gene.	Sanjuan J et al
154682	1979	Studies on human blood platelets in affective disorder.	Scott M et al
15108187	2004	Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.	Sen S et al
19032574	2009	Characterization of a functional polymorphism in the 3' UTR of SLC6A4 and its association with drinking intensity.	Seneviratne C et al
18663369	2010	Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR).	Strug LJ et al
22832526	2011	Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.	Sugawara H et al
11559314	2001	The 5-HTTPRS/L polymorphism and aggressive behavior in Alzheimer disease.	Sukonick DL et al
15995945	2005	Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.	Sutcliffe JS et al
7523405	1994	The effect of N-linked glycosylation on activity of the Na(+)- and Cl(-)-dependent serotonin transporter expressed using recombinant baculovirus in insect cells.	Tate CG et al
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27087270	2016	Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder.	Tyrer AE et al
16009349	2005	Allelic variation in the serotonin transporter (5HTT) gene contributes to idiopathic pulmonary hypertension in children.	Vachharajani A et al
18445138	2008	Functional variation in the 3' untranslated region of the serotonin transporter in human and rhesus macaque.	Vallender EJ et al
24229495	2014	Gender-specific association of the SLC6A4 and DRD2 gene variants in bipolar disorder.	Wang TY et al
24937096	2014	Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles.	Wankerl M et al
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18055562	2008	A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder.	Wendland JR et al
14593433	2003	A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder.	Willeit M et al
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24649276	2013	Expression of aquaporin-1 is a poor prognostic factor for stage II and III colon cancer.	Yoshida T et al
18077373	2007	Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.	Zhang Y 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 ID	Transcript ID	Uniprot
ENSG00000108576	ENST00000261707	P31645
ENSG00000108576	ENST00000394821	J3KPR9
ENSG00000108576	ENST00000401766	P31645
ENSG00000108576	ENST00000579221	J3QKP3
ENSG00000108576	ENST00000650711	P31645

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Serotonergic synapse	KEGG	hsa04726
Neuronal System	REACTOME	R-HSA-112316
Transmission across Chemical Synapses	REACTOME	R-HSA-112315
Neurotransmitter Clearance In The Synaptic Cleft	REACTOME	R-HSA-112311
Serotonin clearance from the synaptic cleft	REACTOME	R-HSA-380615

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA10074	escitalopram	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous		PD	19272758, 19567893, 20212518, 23095326, 24014145
PA124	CYP2C19	Gene	DataAnnotation	associated
PA128	CYP2D6	Gene	DataAnnotation	associated
PA128406954	Weight gain	Disease	VariantAnnotation	associated		PD
PA164713257	Selective serotonin reuptake inhibitors	Chemical	ClinicalAnnotation, Literature, MultilinkAnnotation, VariantAnnotation	associated		PD	17414739, 19204908, 22086748, 24930681, 28639488
PA164784024	peginterferon alfa-2b	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD
PA165860788	evodiamine	Chemical	VariantAnnotation	associated	PK		21647174
PA165860812	berberine	Chemical	VariantAnnotation	associated	PK		21647174
PA166048714	Pregnancy	Disease	VariantAnnotation	associated		PD	28639488
PA193	HTR2A	Gene	DataAnnotation	associated
PA27093	CYP1A2	Gene	DataAnnotation	associated
PA443309	Alcoholism	Disease	ClinicalAnnotation, VariantAnnotation	associated		PD	21247998, 31595439
PA443853	Dementia	Disease	VariantAnnotation	associated		PD
PA443928	Dizziness	Disease	VariantAnnotation	associated		PD	23859574
PA443937	Drug Toxicity	Disease	ClinicalAnnotation	associated		PD	20031235, 23859574
PA444367	Heart Defects, Congenital	Disease	VariantAnnotation	associated		PD	28639488
PA444624	Sleep Initiation and Maintenance Disorders	Disease	VariantAnnotation	associated		PD	14573314
PA445043	Opioid-Related Disorders	Disease	ClinicalAnnotation, VariantAnnotation	associated		PD	29333880
PA445048	Nausea	Disease	VariantAnnotation	not associated		PD	12208565, 17697394
PA445208	Pain	Disease	ClinicalAnnotation	associated		PD	32432768
PA445452	Psychomotor Agitation	Disease	VariantAnnotation	associated		PD	14573314
PA445876	Tobacco Use Disorder	Disease	ClinicalAnnotation	associated		PD	21658141
PA446863	Hepatitis C, Chronic	Disease	ClinicalAnnotation, VariantAnnotation	associated		PD
PA447197	Attention Deficit Disorder with Hyperactivity	Disease	VariantAnnotation	not associated		PD	17948872
PA447207	Depressive Disorder	Disease	ClinicalAnnotation, VariantAnnotation	ambiguous		PD	11543734, 16515395, 17697394, 19272758, 19451862, 19567893, 20212518, 23510446, 24014145
PA447209	Mood Disorders	Disease	ClinicalAnnotation, VariantAnnotation	ambiguous		PD	10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16874005, 17146470, 17853254, 17914325, 18983505, 18987562, 19606452, 19800133, 23288236
PA447211	Obsessive-Compulsive Disorder	Disease	VariantAnnotation	not associated		PD	12082589
PA447212	Panic Disorder	Disease	VariantAnnotation	ambiguous		PD	16034444, 16822601, 19259652, 19800133, 21688171
PA447216	Schizophrenia	Disease	VariantAnnotation	associated		PD	20031235, 20452607
PA447278	Depression	Disease	ClinicalAnnotation, DataAnnotation, VariantAnnotation	ambiguous		PD	10683861, 12374640, 16302021, 17018806, 18253134, 19272758, 19567893, 20212518, 24014145
PA447321	Depressive Disorder, Major	Disease	ClinicalAnnotation, DataAnnotation, VariantAnnotation	ambiguous	PK	PD	10653220, 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
PA448073	ethanol	Chemical	ClinicalAnnotation	associated		PD	31595439
PA448685	buprenorphine	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	29333880
PA448687	bupropion	Chemical	ClinicalAnnotation	associated		PD	21658141
PA449015	citalopram	Chemical	ClinicalAnnotation, Pathway, VariantAnnotation	ambiguous		PD	14624186, 17606812, 18618621, 19468717, 19741567, 19996755, 20640435, 23510446, 23973251
PA449048	clomipramine	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	10867985
PA449061	clozapine	Chemical	VariantAnnotation	associated		PD	20452607
PA449673	fluoxetine	Chemical	ClinicalAnnotation, Pathway, VariantAnnotation	ambiguous		PD	10683861, 12476327, 14573314, 15993855, 16302021, 17018806, 19468717, 19741567, 20584552, 20640435, 22885912, 27439447
PA449690	fluvoxamine	Chemical	ClinicalAnnotation, Pathway, VariantAnnotation	ambiguous		PD	11543734, 11817517, 12082589, 12208565, 12374640, 15274037, 15812265, 16874005, 19741567, 23288236, 9857976
PA449841	haloperidol	Chemical	MultilinkAnnotation, VariantAnnotation	associated		PD	20031235, 27023437
PA450401	methadone	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	29333880
PA450464	methylphenidate	Chemical	VariantAnnotation	not associated		PD	17948872
PA450522	mirtazapine	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous		PD	15520364
PA450550	morphine	Chemical	ClinicalAnnotation	associated		PD	32432768
PA450657	nortriptyline	Chemical	VariantAnnotation	not associated		PD	11027924, 19567893
PA450688	olanzapine	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	20031235, 23859574
PA450705	ondansetron	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	21247998
PA450801	paroxetine	Chemical	ClinicalAnnotation, Pathway, VariantAnnotation	ambiguous		PD	10653220, 10683861, 11027924, 15274037, 15520364, 15812265, 16034444, 16822601, 16874005, 17697394, 17853254, 17914325, 18983505, 18987562, 19259652, 19468717, 19606452, 19741567, 19800133, 20640435, 21688171, 23288236
PA450966	pindolol	Chemical	VariantAnnotation	not associated		PD	9857976
PA451201	quetiapine	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	20031235, 23859574
PA451241	ribavirin	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD
PA451257	risperidone	Chemical	ClinicalAnnotation, VariantAnnotation	associated		PD	20031235, 23859574
PA451333	sertraline	Chemical	ClinicalAnnotation, Pathway, VariantAnnotation	ambiguous	PK	PD	12955294, 16580768, 17018806, 18452396, 19741567, 19800133, 19825907, 21962566, 22885912
PA451866	venlafaxine	Chemical	VariantAnnotation	not associated		PD	19468717, 24014145
PA452229	antidepressants	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous		PD	16515395, 17146470, 18253134, 19451862
PA452233	antipsychotics	Chemical	VariantAnnotation	associated		PD	20031235

References

Pubmed ID	Year	Title	Citations
37070394	2024	Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.	1
38103452	2024	DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.	0
38288388	2024	Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation.	0
38361316	2024	SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health.	1
38465822	2024	[The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression].	0
38753762	2024	PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs.	0
38928372	2024	Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses.	0
37070394	2024	Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.	1
38103452	2024	DNA methylation levels of the serotonin transporter gene are not associated with the outcome of highly standardized one-session exposure-based fear treatment.	0
38288388	2024	Tailoring Type II Diabetes Treatment: Investigating the Effect of 5-HTT Polymorphisms on HbA1c Levels after Metformin Initiation.	0
38361316	2024	SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health.	1
38465822	2024	[The association of polymorphisms of the serotonin transporter gene SLC6A4 with depression].	0
38753762	2024	PPARgamma dependent PEX11beta counteracts the suppressive role of SIRT1 on neural differentiation of HESCs.	0
38928372	2024	Connection Failure: Differences in White Matter Microstructure Are Associated with 5-HTTLPR but Not with Risk Seeking for Losses.	0
36649260	2023	Unravelling 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/css/lib/css/gene-explorer/