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SLC6A4 (solute carrier family 6 member 4)

Written2019-03Rafig Gurbanov, Berkay Kalkanci
Department of Molecular Biology and Genetics (RG); Bilecik Seyh Edebali University, Department of Biotechnology (BK), Bilecik Seyh Edebali University, Biotechnology Application and Research Center, Bilecik, Turkey; rafig.gurbanov@bilecik.edu.tr; berkaykalkancii@gmail.com

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.

Keywords Solute Carrier Family 6 Member 4 (SLC6A4), Serotonin (5-HT), Serotonin transporter protein (5-HTT), Anxiety, Alcoholism, Hypertension, Mental Disorders.

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Identity

Alias_namesHTT
OCD1
solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
5-hydroxytryptamine (serotonin) transporter
obsessive-compulsive disorder 1
solute carrier family 6 (neurotransmitter transporter), member 4
Alias_symbol (synonym)5-HTT
SERT1
Other alias5-HTTLPR
5HTT
SERT
hSERT
HGNC (Hugo) SLC6A4
LocusID (NCBI) 6532
Atlas_Id 49951
Location 17q11.2  [Link to chromosome band 17q11]
Location_base_pair Starts at 30194319 and ends at 30235968 bp from pter ( according to hg19-Feb_2009)  [Mapping SLC6A4.png]
 
  Figure 1. Genomic location of SLC6A4 (Chromosome 17 - NC_000017.11 Reference GRCh38.p12 Primary Assembly)
 
  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)
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PIP4K2B/SLC6A4

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)
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).

Protein

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).
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).
 
  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).
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-HT's 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
#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

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 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 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 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 Alzheimer's 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 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 individual's 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 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 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 3'UTR 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 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 Panic Disorder (PD)
Note The rs3813034 variant in the 3'UTR 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 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 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).
  

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Citation

This paper should be referenced as such :
Gurbanov R, Kalkanci B
SLC6A4 (solute carrier family 6 member 4);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/SLC6A4ID49951ch17q11.html

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(17;17)(q11;q12) PIP4K2B/SLC6A4

External links

Nomenclature
HGNC (Hugo)SLC6A4   11050
Cards
AtlasSLC6A4ID49951ch17q11
Entrez_Gene (NCBI)SLC6A4  6532  solute carrier family 6 member 4
Aliases5-HTT; 5-HTTLPR; 5HTT; HTT; 
OCD1; SERT; SERT1; hSERT
GeneCards (Weizmann)SLC6A4
Ensembl hg19 (Hinxton)ENSG00000108576 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000108576 [Gene_View]  ENSG00000108576 [Sequence]  chr17:30194319-30235968 [Contig_View]  SLC6A4 [Vega]
ICGC DataPortalENSG00000108576
TCGA cBioPortalSLC6A4
AceView (NCBI)SLC6A4
Genatlas (Paris)SLC6A4
WikiGenes6532
SOURCE (Princeton)SLC6A4
Genetics Home Reference (NIH)SLC6A4
Genomic and cartography
GoldenPath hg38 (UCSC)SLC6A4  -     chr17:30194319-30235968 -  17q11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SLC6A4  -     17q11.2   [Description]    (hg19-Feb_2009)
GoldenPathSLC6A4 - 17q11.2 [CytoView hg19]  SLC6A4 - 17q11.2 [CytoView hg38]
ImmunoBaseENSG00000108576
Mapping of homologs : NCBISLC6A4 [Mapview hg19]  SLC6A4 [Mapview hg38]
OMIM164230   182138   
Gene and transcription
Genbank (Entrez)AA700070 AK308014 AK309538 AK313166 AU138385
RefSeq transcript (Entrez)NM_001045
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SLC6A4
Cluster EST : UnigeneHs.134662 [ NCBI ]
CGAP (NCI)Hs.134662
Alternative Splicing GalleryENSG00000108576
Gene ExpressionSLC6A4 [ NCBI-GEO ]   SLC6A4 [ EBI - ARRAY_EXPRESS ]   SLC6A4 [ SEEK ]   SLC6A4 [ MEM ]
Gene Expression Viewer (FireBrowse)SLC6A4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6532
GTEX Portal (Tissue expression)SLC6A4
Human Protein AtlasENSG00000108576-SLC6A4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP31645   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP31645  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP31645
Splice isoforms : SwissVarP31645
PhosPhoSitePlusP31645
Domaine pattern : Prosite (Expaxy)NA_NEUROTRAN_SYMP_1 (PS00610)    NA_NEUROTRAN_SYMP_2 (PS00754)    NA_NEUROTRAN_SYMP_3 (PS50267)   
Domains : Interpro (EBI)Na/ntran_symport    Na/ntran_symport_serotonin_N    SNS_sf   
Domain families : Pfam (Sanger)5HT_transport_N (PF03491)    SNF (PF00209)   
Domain families : Pfam (NCBI)pfam03491    pfam00209   
Conserved Domain (NCBI)SLC6A4
DMDM Disease mutations6532
Blocks (Seattle)SLC6A4
PDB (RSDB)5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
PDB Europe5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
PDB (PDBSum)5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
PDB (IMB)5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
Structural Biology KnowledgeBase5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
SCOP (Structural Classification of Proteins)5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
CATH (Classification of proteins structures)5I6X    5I6Z    5I71    5I73    5I74    5I75    6AWN    6AWO    6AWP    6AWQ   
SuperfamilyP31645
Human Protein Atlas [tissue]ENSG00000108576-SLC6A4 [tissue]
Peptide AtlasP31645
HPRD01640
IPIIPI00790986   IPI00797748   
Protein Interaction databases
DIP (DOE-UCLA)P31645
IntAct (EBI)P31645
FunCoupENSG00000108576
BioGRIDSLC6A4
STRING (EMBL)SLC6A4
ZODIACSLC6A4
Ontologies - Pathways
QuickGOP31645
Ontology : AmiGOresponse to hypoxia  serotonin:sodium symporter activity  serotonin:sodium symporter activity  serotonin:sodium symporter activity  serotonin:sodium symporter activity  protein binding  cytosol  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  serotonin transport  response to nutrient  memory  circadian rhythm  monoamine transmembrane transporter activity  response to toxic substance  endosome membrane  positive regulation of gene expression  endomembrane system  positive regulation of serotonin secretion  monoamine transport  myosin binding  syntaxin-1 binding  Rab GTPase binding  cocaine binding  negative regulation of cerebellar granule cell precursor proliferation  negative regulation of synaptic transmission, dopaminergic  response to estradiol  social behavior  neurotransmitter biosynthetic process  vasoconstriction  response to drug  sperm ejaculation  protein homodimerization activity  neuron projection  membrane raft  negative regulation of neuron differentiation  positive regulation of cell cycle  negative regulation of organ growth  metal ion binding  brain morphogenesis  nitric-oxide synthase binding  actin filament binding  protein complex oligomerization  protein homooligomerization  serotonin binding  serotonin uptake  serotonin uptake  serotonin uptake  transmembrane transport  cellular response to retinoic acid  cellular response to cGMP  regulation of thalamus size  integral component of postsynaptic membrane  integral component of presynaptic membrane  serotonergic synapse  
Ontology : EGO-EBIresponse to hypoxia  serotonin:sodium symporter activity  serotonin:sodium symporter activity  serotonin:sodium symporter activity  serotonin:sodium symporter activity  protein binding  cytosol  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  serotonin transport  response to nutrient  memory  circadian rhythm  monoamine transmembrane transporter activity  response to toxic substance  endosome membrane  positive regulation of gene expression  endomembrane system  positive regulation of serotonin secretion  monoamine transport  myosin binding  syntaxin-1 binding  Rab GTPase binding  cocaine binding  negative regulation of cerebellar granule cell precursor proliferation  negative regulation of synaptic transmission, dopaminergic  response to estradiol  social behavior  neurotransmitter biosynthetic process  vasoconstriction  response to drug  sperm ejaculation  protein homodimerization activity  neuron projection  membrane raft  negative regulation of neuron differentiation  positive regulation of cell cycle  negative regulation of organ growth  metal ion binding  brain morphogenesis  nitric-oxide synthase binding  actin filament binding  protein complex oligomerization  protein homooligomerization  serotonin binding  serotonin uptake  serotonin uptake  serotonin uptake  transmembrane transport  cellular response to retinoic acid  cellular response to cGMP  regulation of thalamus size  integral component of postsynaptic membrane  integral component of presynaptic membrane  serotonergic synapse  
Pathways : KEGGSerotonergic synapse   
REACTOMEP31645 [protein]
REACTOME PathwaysR-HSA-380615 [pathway]   
NDEx NetworkSLC6A4
Atlas of Cancer Signalling NetworkSLC6A4
Wikipedia pathwaysSLC6A4
Orthology - Evolution
OrthoDB6532
GeneTree (enSembl)ENSG00000108576
Phylogenetic Trees/Animal Genes : TreeFamSLC6A4
HOGENOMP31645
Homologs : HomoloGeneSLC6A4
Homology/Alignments : Family Browser (UCSC)SLC6A4
Gene fusions - Rearrangements
Fusion : MitelmanPIP4K2B/SLC6A4 [17q12/17q11.2]  [t(17;17)(q11;q12)]  
Fusion PortalPIP4K2B 17q12 SLC6A4 17q11.2 BRCA
Fusion : FusionGDB27267    34437    36165    39173   
Fusion : Fusion_HubCPD--SLC6A4    PIP4K2B--SLC6A4    SLC39A11--SLC6A4    SLC6A4--TOB1    SSH2--SLC6A4   
Fusion : QuiverSLC6A4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSLC6A4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SLC6A4
dbVarSLC6A4
ClinVarSLC6A4
1000_GenomesSLC6A4 
Exome Variant ServerSLC6A4
ExAC (Exome Aggregation Consortium)ENSG00000108576
GNOMAD BrowserENSG00000108576
Varsome BrowserSLC6A4
Genetic variants : HAPMAP6532
Genomic Variants (DGV)SLC6A4 [DGVbeta]
DECIPHERSLC6A4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSLC6A4 
Mutations
ICGC Data PortalSLC6A4 
TCGA Data PortalSLC6A4 
Broad Tumor PortalSLC6A4
OASIS PortalSLC6A4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSLC6A4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSLC6A4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SLC6A4
DgiDB (Drug Gene Interaction Database)SLC6A4
DoCM (Curated mutations)SLC6A4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SLC6A4 (select a term)
intoGenSLC6A4
NCG5 (London)SLC6A4
Cancer3DSLC6A4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM164230    182138   
Orphanet
DisGeNETSLC6A4
MedgenSLC6A4
Genetic Testing Registry SLC6A4
NextProtP31645 [Medical]
TSGene6532
GENETestsSLC6A4
Target ValidationSLC6A4
Huge Navigator SLC6A4 [HugePedia]
snp3D : Map Gene to Disease6532
BioCentury BCIQSLC6A4
ClinGenSLC6A4 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6532
Chemical/Pharm GKB GenePA312
Clinical trialSLC6A4
Miscellaneous
canSAR (ICR)SLC6A4 (select the gene name)
DataMed IndexSLC6A4
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSLC6A4
EVEXSLC6A4
GoPubMedSLC6A4
iHOPSLC6A4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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