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Gene Review

SLC6A4  -  solute carrier family 6 (neurotransmitter...

Homo sapiens

Synonyms: 5-HTT, 5-HTTLPR, 5HT transporter, 5HTT, HTT, ...
 
 
 

Disease relevance of SLC6A4

 

Psychiatry related information on SLC6A4

  1. SLC6A4 and the Development of Aggressive Behaviors: The short variant of the serotonin transporter promoter gene has been found to positively correlate with aggressive behavior in a general sample of middle school children [6]. It has also been linked to aggressive conducts in the presence of attention deficit disorder in males [7], and with impulsive violent behavior in early onset alcoholism.
  2. Other associations:
  • Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders [2].
  • Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium [8].
  • Current studies have found associations of SLC6A4 polymorphisms with several psychiatric traits including bipolar affective disorder (BPD) in various populations; however, studies with contradictory results were also reported [9].
  • Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN [10].
  • The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown [11].
 

High impact information on SLC6A4

  • We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter [12].
  • Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy [13].
  • Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region [14].
  • The Silastic device, dubbed SERT (sustained ethanol release tube), holds 0.35 milliliter of 95 percent ethanol (by volume) and is implanted under the skin of the back where it releases ethanol for up to 12 hours, with no observable tissue damage [15].
  • These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins [16].
 

Chemical compound and disease context of SLC6A4

 

Biological context of SLC6A4

  • In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele [19].
  • Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism [19].
  • There was no effect of SLC6A4 genotype upon serotonin transporter binding [20].
  • To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004 [21].
  • Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals [22].
 

Anatomical context of SLC6A4

 

Associations of SLC6A4 with chemical compounds

  • Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04) [27].
  • In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated [28].
  • Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene [29].
  • From this series, the dimethylated derivatives 13, 14a, 14b, 16, and 20 were radiolabeled with carbon-11 and their log P(7.4) was calculated as a measure of their potential brain penetrance as positron emission tomography SERT imaging agents [30].
  • Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4) [31].
 

Physical interactions of SLC6A4

  • With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth [32].
  • We also examine whether ITGB3 might interact with SLC6A4 to contribute to autism susceptibility [33].
  • Using a yeast one-hybrid screen, we found the transcription factor Y box binding protein 1 (YB-1) interacts with the 5-HTT VNTR [34].
  • The present data show that the SNARE protein syntaxin 1A binds the N-terminal tail of SERT, and this interaction regulates two SERT-conducting states [35].
  • In addition, SERT was found to form a complex with SCAMP2 as demonstrated by co-immunoprecipitation from a heterologous expression system and from rat brain homogenate [36].
 

Regulatory relationships of SLC6A4

 

Other interactions of SLC6A4

 

Analytical, diagnostic and therapeutic context of SLC6A4

  • CONCLUSIONS: This study suggested that a particular SLC6A4 haplotype harboring functional sequence variant could play a significant role in BPD etiology in Taiwan. However, due to its modest sample size, the conclusion is not final and should be confirmed in the future studies [9].
  • Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17 [44].
  • A cDNA encoding a serotonin transporter (5-HTT) in the human dorsal raphe nucleus was isolated and sequenced using cross-species amplification of human 5-HTT partial cDNA by the polymerase chain reaction (PCR) and the RACE-PCR procedure, designed for rapid amplification of 3' and 5' cDNA ends [45].
  • Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM) [46].
  • The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls [47].

References

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