SLC6A4 (solute carrier family 6 member 4)

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SLC6A4 (solute carrier family 6 member 4)

Written	2019-03	Rafig 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.

(Note : for Links provided by Atlas : click)

Identity

Alias_names	HTT
	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 alias	5-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 30235697 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)

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).

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).

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 BP_ND), 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 BP_ND by 12% in the ACC with respect to placebo, whereas in the fall, no significant change in 5-HTT BP_ND was measured. In this context, it has been reported that 5-HTT BP_ND 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 BP_ND levels. The study reported a significant increase in 5-HTT BP_ND in different brain regions (including ACC and PFC) especially in severe SAD during winter. The 5-HTT BP_ND 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).

	Nomenclature
HGNC (Hugo)	SLC6A4 11050
	Cards
Atlas	SLC6A4ID49951ch17q11
Entrez_Gene (NCBI)	SLC6A4 6532 solute carrier family 6 member 4
Aliases	5-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] chr17:30194319-30235697 [Contig_View] SLC6A4 [Vega]
ICGC DataPortal	ENSG00000108576
TCGA cBioPortal	SLC6A4
AceView (NCBI)	SLC6A4
Genatlas (Paris)	SLC6A4
WikiGenes	6532
SOURCE (Princeton)	SLC6A4
Genetics Home Reference (NIH)	SLC6A4
	Genomic and cartography
GoldenPath hg38 (UCSC)	SLC6A4 - chr17:30194319-30235697 - 17q11.2 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	SLC6A4 - 17q11.2 [Description] (hg19-Feb_2009)
GoldenPath	SLC6A4 - 17q11.2 [CytoView hg19] SLC6A4 - 17q11.2 [CytoView hg38]
Genome Data Viewer NCBI	SLC6A4 [Mapview hg19]
OMIM	164230 182138 607834
	Gene and transcription
Genbank (Entrez)	AA700070 AK308014 AK309538 AK313166 AU138385
RefSeq transcript (Entrez)	NM_001045
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	SLC6A4
Alternative Splicing Gallery	ENSG00000108576
Gene Expression	SLC6A4 [ NCBI-GEO ] SLC6A4 [ EBI - ARRAY_EXPRESS ] SLC6A4 [ SEEK ] SLC6A4 [ MEM ]
Gene Expression Viewer (FireBrowse)	SLC6A4 [ Firebrowse - Broad ]
Genevisible	Expression of SLC6A4 in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	6532
GTEX Portal (Tissue expression)	SLC6A4
Human Protein Atlas	ENSG00000108576-SLC6A4 [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P31645 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	P31645 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	P31645
Splice isoforms : SwissVar	P31645
PhosPhoSitePlus	P31645
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 mutations	6532
PDB (RSDB)	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
PDB Europe	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
PDB (PDBSum)	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
PDB (IMB)	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
Structural Biology KnowledgeBase	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
SCOP (Structural Classification of Proteins)	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
CATH (Classification of proteins structures)	5I6X 5I6Z 5I71 5I73 5I74 5I75 6AWN 6AWO 6AWP 6AWQ 6DZV 6DZW 6DZY 6DZZ
Superfamily	P31645
Human Protein Atlas [tissue]	ENSG00000108576-SLC6A4 [tissue]
Peptide Atlas	P31645
HPRD	01640
IPI	IPI00790986 IPI00797748
	Protein Interaction databases
DIP (DOE-UCLA)	P31645
IntAct (EBI)	P31645
FunCoup	ENSG00000108576
BioGRID	SLC6A4
STRING (EMBL)	SLC6A4
ZODIAC	SLC6A4
	Ontologies - Pathways
QuickGO	P31645
Ontology : AmiGO	"response to hypoxia serotonin:sodium symporter activity serotonin:sodium symporter activity serotonin:sodium symporter activity protein binding plasma membrane plasma membrane plasma membrane focal adhesion 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 syntaxin-1 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 identical protein binding neuron projection membrane raft synapse 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 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-EBI	"response to hypoxia serotonin:sodium symporter activity serotonin:sodium symporter activity serotonin:sodium symporter activity protein binding plasma membrane plasma membrane plasma membrane focal adhesion 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 syntaxin-1 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 identical protein binding neuron projection membrane raft synapse 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 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 : KEGG	Serotonergic synapse
REACTOME	P31645 [protein]
REACTOME Pathways	R-HSA-380615 [pathway]
NDEx Network	SLC6A4
Atlas of Cancer Signalling Network	SLC6A4
Wikipedia pathways	SLC6A4
	Orthology - Evolution
OrthoDB	6532
GeneTree (enSembl)	ENSG00000108576
Phylogenetic Trees/Animal Genes : TreeFam	SLC6A4
HOGENOM	P31645
Homologs : HomoloGene	SLC6A4
Homology/Alignments : Family Browser (UCSC)	SLC6A4
	Gene fusions - Rearrangements
Fusion : Mitelman	PIP4K2B/SLC6A4 [17q12/17q11.2]
Fusion Portal	PIP4K2B 17q12 SLC6A4 17q11.2 BRCA
Fusion : Fusion_Hub	CPD--SLC6A4 PIP4K2B--SLC6A4 SLC39A11--SLC6A4 SLC6A4--TOB1 SSH2--SLC6A4
Fusion : Quiver	SLC6A4
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	SLC6A4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)	SLC6A4
dbVar	SLC6A4
ClinVar	SLC6A4
1000_Genomes	SLC6A4
Exome Variant Server	SLC6A4
GNOMAD Browser	ENSG00000108576
Varsome Browser	SLC6A4
Genetic variants : HAPMAP	6532
Genomic Variants (DGV)	SLC6A4 [DGVbeta]
DECIPHER	SLC6A4 [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	SLC6A4
	Mutations
ICGC Data Portal	SLC6A4
TCGA Data Portal	SLC6A4
Broad Tumor Portal	SLC6A4
OASIS Portal	SLC6A4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMIC	SLC6A4 [overview] [genome browser] [tissue] [distribution]
Somatic Mutations in Cancer : COSMIC3D	SLC6A4
Mutations and Diseases : HGMD	SLC6A4
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
BioMuta	select 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)
intoGen	SLC6A4
NCG6 (London)	select SLC6A4
Cancer3D	SLC6A4 (select the gene name)
Impact of mutations	[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	164230 182138 607834
Orphanet
DisGeNET	SLC6A4
Medgen	SLC6A4
Genetic Testing Registry	SLC6A4
NextProt	P31645 [Medical]
TSGene	6532
GENETests	SLC6A4
Open Targets Genetics	ENSG00000108576 [validation]
snp3D : Map Gene to Disease	6532
BioCentury BCIQ	SLC6A4
ClinGen	SLC6A4 (curated)
	Clinical trials, drugs, therapy
Protein Interactions : CTD	6532
Pharm GKB Gene	PA312
Pharm GKB Pathways	PA161749006 PA166014758
Clinical trial	SLC6A4
	Miscellaneous
canSAR (ICR)	SLC6A4 (select the gene name)
Harmonizome	SLC6A4
DataMed Index	SLC6A4
	Probes
	Litterature
PubMed	499 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
CoreMine	SLC6A4
EVEX	SLC6A4

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed