Several studies have found genetic association between the SLC6A4 gene and autism in AGRE, CPEA, French-Caucasian, Portuguese and several mixed US population cohorts. However, several other studies found no genetic association between the SLC6A4 gene and autism in AGRE, SARC, US and Chinese Han population cohorts. Separately, genetic association has been found between the SLC6A4 gene and pervasive developmental disorder (PDD) in a Dutch population cohort. In addition, rare mutations in the SLC6A4 gene have been identified in individuals with ASD (Neale et al., 2012).
Molecular Function
The encoded protein has serotonin transporter activity, serotonin:sodium symport er activity.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Evidence of linkage between the serotonin transporter and autistic disorder.
The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner
76 children with high-functioning autism (HFA, IQ>80), 78 siblings, and 99 controls (all of Caucasian descent) collected in Dept. of Child and Adolescent Psychiatry at Univ. of Zurich
Slc6a4 Ala56 (a constitutively active mutation)-expressing mice have GI defects, including enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in Slc6a4 knockout mice and in progeny of WT dams given the SERT antagonist fluoxetine.
References
Type
Title
Author, Year
Primary
Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A construct comprising 9 kilobases of genomic DNA was engineered to delete the first coding exon of the Slc6a4 gene.
Allele Type: Targeted (Knock out)
Strain of Origin: Not Specified
Genetic Background: 129S6/SvEv
ES Cell Line: 129S6/SvEv
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A construct comprising 9 kilobases of genomic DNA was engineered to delete the first coding exon of the Slc6a4 gene.
Allele Type: Targeted (Knock out)
Strain of Origin: Not Specified
Genetic Background: 129S6/SvEv
ES Cell Line: 129S6/SvEv
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted disruption of exon 2 of Slc6a4 gene with PGK neomycin-poly A expression casette.
Allele Type: Targeted (Knock out)
Strain of Origin: C57BL/6
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous dams carrying targeted disruption of exon 2 of Slc6a4 gene with PGK neomycin-poly A expression casette randomly assigned to stress paradigm subjected to chronic variable stress from gestational day 6 to parturition.
Allele Type: Targeted (Knock out)
Strain of Origin: C57BL/6
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The replacement of Gly56 with Ala56 at the exon 2 of Slc6a4 is done by homologous recombination between genome and the targeting construct containing exons 2 to 5 of Slc6a4 gene with a floxed Neomycin-resistance cassette inserted between exons 4 and 5.
Allele Type: Targeted (Knock In)
Strain of Origin: Not specified
Genetic Background: 129S6/SvEvTac
ES Cell Line: 129S6/SvEvTac
Mutant ES Cell Line: Not specified
Model Source: Not specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The second exon of the SERT gene has been replaced by homologous recombination with a phosphoglycerine kinase-neo gene cassette.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Not specified
Model Source: Not specified
Model Type:
Pharmaceutical intervention
Model Genotype:
Homozygous
Mutation:
A sympathetic nervous system blocker, 6-hydroxydopamine (6-OHDA), is administered by Intraperitoneal injection (100 mg/kg in 0.5 % ascorbic acid) in the Slc6a4 muntant mice (PMID: 27111230).
Allele Type: Targeted (Knock Out)
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The replacement of Gly56 with Ala56 at the exon 2 of Slc6a4 is done by homologous recombination between genome and the targeting construct containing exons 2 to 5 of Slc6a4 gene with a floxed Neomycin-resistance cassette inserted between exons 4 and 5.
Allele Type: Targeted (Knock In)
Strain of Origin: Not specified
Genetic Background: 129S6/SvEvTac
ES Cell Line: 129S6/SvEvTac
Mutant ES Cell Line: Not specified
Model Source: Not specified
Description: Decresed neuron number demonstrated by significantly fewer 5-ht immunopositive neurons in the dorse raphe nucleus
Exp Paradigm: Immunohistochemistry and stereologic counting techniques
Description: Abnormal action potential firing; no differences in waveform shape; fourfold reduction in average firing rate
Exp Paradigm: Extracellular recording of activity in the dorsal raphe nucleus
Description: Increased grooming indicated by more grooming bouts, episodes, total duration, total transitions, lower latency to groom
Exp Paradigm: Automated monitoring of animals in home cage
Description: Increased grooming bouts, episodes and total transitions with increased paw licking behavior, rostral grooming and trostral transitions frequency
Exp Paradigm: Manual observations of grooming behavior
Description: Enteric gabaergic neurons in the myenteric plexus of the ileum are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: gaba
Description: Total enteric neurons in the submucosal plexus and the myenteric plexus of the ileum are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: huc/d
Description: Enteric gabaergic neurons in the myenteric plexus of the colon are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: gaba
Description: Total enteric neurons in the myenteric plexus of the colon are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: huc/d
Description: Enteric dopaminergic neurons in the submucosal plexus of the ileum are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: th (tyrosine hydroxylase)
Description: The density of serotonergic neurons in the sert ala56 intestine is only about 36% of that found in the intestines of wt littermates
Exp Paradigm: Immunocytochemistry: 5-ht (5-hydroxytryptamine)
Description: Enteric cgrp-immunoreactive neurons in the submucosal plexus of the ileum are significantly less abundant in sert ala56 than in wt mice
Exp Paradigm: Immunocytochemistry: cgrp (calcintonin)
Description: Increased head twitch response to 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (doi)
Exp Paradigm: General observation of head twitch response to 5-ht2a/2c receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (doi)
Description: Decreased social interaction as indicated by failure to show preference for another mouse vs. inanimate object
Exp Paradigm: Three cambered test for sociability
Digestive system function: intestinal barrier: intestinal permeability2
Decreased
Description: Permeability to fitc-dextran in sert ala56 mice is found to be significantly less than that of wt animals; the tight junction between enterocytes is intact in sert ala56 mice
Exp Paradigm: Intestinal permeability test: the concentration of fitc-dextran in blood is measured 2 or 5 hr after gavage; electron microscopy: hrp (i.v. injected)
Digestive system function: gastrointestinal motility2
Decreased
Description: Decreased total gi transit speed in sert ala58 mice relative to wildtype controls
Exp Paradigm: Total gi transit time is estimated as the time required for a nonabsorbable dye carmine red to appear in stool after its gavage into the stomach
Digestive system function: gastrointestinal motility: serotonin induced2
Decreased
Description: Small intestinal transit (sit) is significantly slower in sert ala56 than in wt mice after the injection of exogenous 5-ht
Exp Paradigm: Exogenous 5-ht injection 1.0 mg/kg
Digestive system function: mucosal morphology: mucosal growth2
Decreased
Description: Small intestinal villus height and crypt depth are both significantly less in sert ala56 mice than in wt littermates; the mean number of ki67-positive cells per small intestinal crypt of sert ala56 mice is significantly less than that of wt mice
Exp Paradigm: Measurement of villus height/ crypt depth; immunostaining: ki67
Digestive system function: gastrointestinal motility: peristaltic reflexes2
Decreased
Description: The frequency, velocity, and length of propagation of the colonic peristalsis are all significantly lower in sert ala58 than in wt mice.
Exp Paradigm: In vitro analysis of colonic migrating motor complexes (cmmcs)
In vitro analysis of colonic migrating motor complexes (cmmcs)
Digestive system function: mucosal morphology: mucosal growth2
Decreased
Description: Colon crypt depth is significantly decreased in sert ala56 mice than in wt littermates; the mean number of ki67-positive cells per colonic crypt of sert ala56 mice is significantly less than that of wt mice
Exp Paradigm: Measurement of villus height/ crypt depth; immunostaining: ki67
Digestive system function: gastrointestinal motility2
Decreased
Description: Propulsive colorectal motility is decreased in sert ala56 mice relative to wildtype controls
Exp Paradigm: Measurement of colonic motility
Description: Increased hypothermia response mediated by increased sensitivity to 8-oh-dpat
Exp Paradigm: General observation of hypothermia response to 8-oh-dpat
Description: Increased transcripts of tryptophan hydroxylases, tph1 and tph2, in sert ala56 intestines when comparing to wildtype controls
Exp Paradigm: Quantitative pcr (qrt-pcr): tph1 and tph2
Description: Total enteric neurons in the submucosal plexus and the myenteric plexus of the ileum are significantly more abundant in slc6a4 ko than in wt mice
Exp Paradigm: Immunocytochemistry: anna-1 (anti-neuronal nuclear)
Description: Enteric gabaergic neurons in the myenteric plexus of the ileum are significantly more abundant in slc6a4 ko than in wt mice
Exp Paradigm: Immunocytochemistry: gaba
Description: Enteric dopaminergic neurons in the submucosal plexus of the ileum are significantly more abundant in slc6a4 ko than in wt mice
Exp Paradigm: Immunocytochemistry: th (tyrosine hydroxylase)
Description: Enteric cgrp-immunoreactive neurons in the submucosal plexus of the ileum are significantly more abundant in slc6a4 ko than in wt mice
Exp Paradigm: Immunocytochemistry: cgrp (calcintonin)
Description: Serotonergic neurites (axons) appear to ramify more extensively in slc6a4 ko than in wt gut
Exp Paradigm: Immunocytochemistry: 5-ht (5-hydroxytryptamine)
Digestive system function: gastrointestinal motility1
Decreased
Description: Decreased small intestinal transit relative to wildtype controls
Exp Paradigm: Small bowel transit is evaluated following the gavage of rhodamine b dextran in methylcellulose. the geometric center of the rhodamine b dextran in the intestine is determined
Digestive system function: intestinal barrier: intestinal permeability1
Increased
Description: Permeability to fitc-dextran in the slc6a4 mice is increased relative to the wildtype controls
Exp Paradigm: Intestinal permeability test: the concentration of fitc-dextran in blood is measured 2 or 5 hr after gavage
Digestive system function: gastrointestinal motility: peristaltic reflexes1
Decreased
Description: The length of propagation of the colonic peristalsis is significantly shorter in slc6a4 ko than in wt mice while the frequency and velocity remain no changed
Exp Paradigm: Measurement of colonic motility
Digestive system function: mucosal morphology: mucosal growth1
Increased
Description: Small intestinal villus height and crypt depth are both significantly increased in the slc6a4 ko mice than in the wildtype controls
Exp Paradigm: Measurement of villus height/ crypt depth
Digestive system function: mucosal morphology: mucosal growth1
Increased
Description: Colon crypt depth is significantly increased in the slc6a4 ko mice than in the wildtype controls
Exp Paradigm: Measurement of villus height/ crypt depth
Description: Decreased transcripts of tryptophan hydroxylases, tph1 and tph2, in slc6a4 ko intestines when comparing to wildtype controls
Exp Paradigm: Quantitative pcr (qrt-pcr): tph1 and tph2
Digestive system function: gastrointestinal motility1
Restored
Description: Small intestinal transit is restored by the 6-ohda treatment relative to the wildtype controls
Exp Paradigm: Small bowel transit is evaluated following the gavage of rhodamine b dextran in methylcellulose. the geometric center of the rhodamine b dextran in the intestine is determined
Digestive system function: gastrointestinal motility1
Restored
Description: Propulsive colorectal motility is restored by the 6-ohda treatment in slc6a4 ko mice relative to the wildtype controls
Exp Paradigm: Measurement of colonic motility
Description: Sert ala56 mice show elevated basal 5ht clearance rates compared with controls, indicating hypersensitivity of 5ht receptor activity.
Exp Paradigm: Hippocampal clearance of exogenously applied 5-ht was measured by high-speed chronoamperometry
