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Relevance to Autism

Studies have found rare single gene variations in the NLGN3 gene in autism. However, other studies claimed to find no rare variations in the NLGN3 gene in autism patients, although one of these found several silent variations. One study (Ylisaukko-oja et al., 2005) found a genetic association between an NLGN3 variant and autism in a sample of Finnish autism families, and another study (Yu et al., 2011) found a genetic association between an NLGN3 variant and autism in the Chinese Han population.

Molecular Function

This gene encodes a member of a family of neuronal cell-adhesion proteins located at the postsynaptic side of the synapse. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses.

External Links

       

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.
ASD
Positive Association
A sex-specific association of common variants of neuroligin genes (NLGN3 and NLGN4X) with autism spectrum disorders in a Chinese Han cohort.
ASD
Positive Association
Analysis of four neuroligin genes as candidates for autism.
ASD
Negative Association
No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level.
ASD
Negative Association
Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.
ASD
Negative Association
NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population.
ASD
Negative Association
Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.
ASD
Negative association
Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.
ASD
Negative association
Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.
ASD
Support
Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.
ASD
Support
Using whole-exome sequencing to identify inherited causes of autism.
ASD
Support
Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.
ASD
Support
Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder.
ASD
Support
Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.
ASD, SCZ
Recent Recommendation
Neuroligin trafficking deficiencies arising from mutations in the alpha/beta-hydrolase fold protein family.
Recent Recommendation
Differential expression of neuroligin genes in the nervous system of zebrafish.
Recent Recommendation
A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
Recent Recommendation
A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family.
Recent Recommendation
Expression patterns of neurexin-1 and neuroligins in brain and retina of the chick embryo: Neuroligin-3 is absent in retina.
Recent Recommendation
Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism.
Recent Recommendation
The Arg473Cys-neuroligin-1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons.
Recent Recommendation
Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN171R001 
 Missense 
 C to T 
 Arg451Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN171R002 
 Missense 
 C to T 
 Arg451Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN171R003 
 Silent 
 A to G 
 N/A 
  
  
  
 GEN171R004 
 Silent 
 C to G 
 N/A 
  
  
  
 GEN171R005 
 Silent 
 G to A 
 N/A 
  
  
  
 GEN171R006 
 Silent 
 G to A 
 N/A 
  
  
  
 GEN171R007 
 Silent 
 G to A 
 N/A 
  
  
  
 GEN171R008 
 Silent 
 G to A 
 N/A 
  
  
  
 GEN171R009 
 Silent 
 G to A 
 N/A 
  
  
  
 GEN171R010 
 Missense 
 G2189A 
 Thr632Ala 
 Familial 
 Maternal 
 Multiplex 
 GEN171R011 
 Synonymous 
 C to T 
 Tyr74Tyr 
 Familial 
  
 Multiplex 
 GEN171R012 
 Substitution 
 c.727+47G>C 
 N/A 
 Unknown 
  
 Unknown 
 GEN171R013 
 Coding-synonymous 
 c.1698G>A 
 K566K 
 Unknown 
  
 Unknown 
 GEN171R014 
 Substitution 
  
 Intron 
 Unknown 
  
 Multiplex 
 GEN171R015 
 Substitution 
  
 Intron 
 Unknown 
  
 Multiplex 
 GEN171R016 
 Substitution 
  
 Intron 
 Unknown 
  
 Multiplex 
 GEN171R017 
 Substitution 
  
 Intron 
 Unknown 
  
 Multiplex 
 GEN171R018 
 Substitution 
  
 3'UTR 
 Familial 
 Maternal 
 Multiplex 
 GEN171R019 
 Missense 
 c.962T>C 
 V321A 
 Familial 
 Maternal 
 Simplex 
 GEN171R020 
 Missense 
 c.916G>A 
 V306M 
 Familial 
 Maternal 
 Simplex 
 GEN171R021 
 Frameshift deletion 
 TC>T 
  
 Unknown 
  
 Unknown 
 GEN171R022 
 Missense 
 c.1276G>A 
 G426S 
 De novo 
  
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN171C001 
 Substitution 
 rs11795613 
 G to A 
 N/A 
 Chinese Han 
 Discovery 
 GEN171C002 
 Substitution 
 rs4844285 
 A to G 
 N/A 
 Chinese Han 
 Discovery 
 GEN171C003 
 Substitution 
 rs4844286 
 G to T 
 N/A 
 Chinese Han 
 Discovery 
 GEN171C004 
 Substitution 
 rs5981079 
 C to T 
 N/A 
 Chinese Han 
 Discovery 
 GEN171C005 
 Substitution 
 rs7051529 
 G to A 
 N/A 
 Chinese Han 
 Discovery 



Model Summary

Mutant mice display impaired social interactions; increase in inhibitory synaptic transmission

External Links

AllenBrainAtlas   MGI Logo  Entrez Gene

References

Type
Title
Author, Year
Primary
A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.
Additional
Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice.
Additional
Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism.

NLGN3_1_KI_R451C

Model Type: Genetic
Model Genotype: Other
Mutation: Exon 7 carrying an arginine to cysteine amino acid substitution at position 451 (R451C) replaced the wild type exon 7 using a neo cassette as a selectable marker.
Allele Type: Targeted (knock-in)
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129S1/Sv * 129X1/SvJ * C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

NLGN3_2_KO

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Exons 2 and 3 of Nlgn3 removed by cre-mediated recombination
Allele Type: Targeted (knock-out)
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129S1/Sv * 129X1/SvJ * C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

NLGN3_3_KI_R451C

Model Type: Genetic
Model Genotype: Other
Mutation: A BAC targeting vector with the mutation of CGT (arginine451) to TGC (cysteine451) in exon 6 replaced the wild-type sequence.
Allele Type: Targeted (knock-in)
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: 129S1/Sv * 129X1/SvJ * C57BL/6
ES Cell Line: R1
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

NLGN3_1_KI_R451C

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Spontaneous network driven events2
Decreased
Description: Decreased giant depolarizing potential events in CA3 region of hipocampus after exposure to bumetanide
Exp Paradigm: Whole-cell voltage-clamp recordings from CA3 region of hippocampus after exposure to bumetanide, a selective blocker of the cation-chloride cotransporter NKCC1
 Whole-cell voltage-clamp recordings
 P4-P9
Spontaneous network driven events2
Increased
Description: Increased spontaneous network-driven events indicated by higher frequency of Giant depolarizing potentials in CA3 region of hippocampus
Exp Paradigm: Whole-cell voltage-clamp recordings from CA3 region of hippocampus
 Whole-cell voltage-clamp recordings
 P4-P9
Synaptic plasticity1
Abnormal
Description: Abnormal Synaptic plasticity
Exp Paradigm: Whole cell patch-clamp recordings in layer 2-3 of somtosensory cortex
 Whole cell patch-clamp recordings.
 Unreported
Kinectic Properties2
Abnormal
Description: Abnormal kinetic properties indicated by faster decay time of miniature GABAergic events
 
 P9-P11
Synaptic Transmission2
Abnormal
Description: Abnormal synaptic transmission indicated by enhance basal GABAergic but not glutamatergic transmission
Exp Paradigm: Whole cell voltage clamp recordings of miniature GABAa- and AMPA- mediated postsynaptic currents
 Whole-cell voltage-clamp recordings
 P4-P9
Spontaneous network driven events2
Decreased
Description: Decreased giant depolarizing potential events in CA3 region of hipocampus
Exp Paradigm: Whole-cell voltage-clamp recordings from CA3 region of hippocampus
 Whole-cell voltage-clamp recordings
 P8-9; P10
Gene regulation1
Abnormal
Description: Abnormal neuroligin-1 gene regulation
Exp Paradigm: Quantitative Immunoblotting
 Quantitative Immunoblotting
 3 months
Gene regulation1
Abnormal
Description: Partially Abnormal neuroligin-3 gene regulation
Exp Paradigm: Quantitative Immunoblotting
 Quantitative Immunoblotting
 3 months
GABA release2
Increased
Description: Increased GABA transiet in synaptic cleft indicated by decreased reduction of mGPSCs amplitude after bath application of TPMPA
Exp Paradigm: GABA transients in cleft analysis
 GABA transient in the cleft analysis
 
Gene regulation1
Abnormal
Description: Abnormal inhibitory synapse gene regulation
Exp Paradigm: Quantitative confocal immunofluroscence from CA1 and CA3 regions of hippocampus.
 Immunofluorescence Analysis
 3 months
Social interaction1
Decreased
Description: Reduced social interaction.
Exp Paradigm: Social Interaction
 Social Interaction
 2-4 months
Spatial learning1
Increased
Description: Enhanced spatial learning
Exp Paradigm: Morris water maze
 Morris water maze
 2-4 months
 No Change
 
 
Anxiety1
 No Change
 Elevated plus maze test
 2-4 months
Anxiety1
 No Change
 Open field test
 2-4 months
General Curiosity1
 No Change
 Object preference test
 2-4 months
GABA transporters2
 No change
 
 
GABAa receptor channel number2
 No change
 Peak-scaled non-stationary fluctuation analysis
 
Gene regulation1
 No Change
 Quantitative Immunoblotting
 3 months
Muscle coordination1
 No Change
 Rotarod test.
 2-4 months
Brain morphology1
 No Change
 
 
Brain morphology1
 No Change
 Electron microscopy analysis.
 8 weeks
NMDA/AMPA ratio2
 No change
 Whole-cell voltage-clamp recordings
 P4-P9
Resting membrane potential2
 No change
 Whole-cell voltage-clamp recordings
 P4-P9
Tonic conductance2
 No change
 Shift in holding current
 
 No Change
 
 
 Not Reported: Circadian sleep/wake cycle ,   Communications ,   Developmental profile ,   Emotion ,   Homeostasis ,   Immune response ,   Learning & memory ,   Maternal behavior ,   Motor phenotype ,   Neuroanatomy / Ultrastructure / Cytoarchitecture ,   Repetitive behavior ,   Seizure ,   Sensory ,   Social behavior ,  

NLGN3_2_KO

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Gene regulation1
Abnormal
Description: Abnormal Gene Regulation
Exp Paradigm: Quantitative immunoblotting
 Quantitative immunoblotting
 3 months
Gene regulation1
Abnormal
Description: Abnormal NL-3 gene Regulation
Exp Paradigm: Quantitative immunoblotting
 Quantitative immunoblotting
 3 months
Normal phenotype1
 No Change
 General Observation
 Unreported
Gene regulation1
 No Change
 Immunofluorescence Analysis
 3 months
Gene regulation1
 No Change
 Quantitative immunoblotting
 3 months
Synpactic plasticity1
 No Change
 Whole-cell patch clamp recordings
 Unreported
 Not Reported: Anxiety ,   Circadian sleep/wake cycle ,   Communications ,   Homeostasis ,   Immune response ,   Learning & memory ,   Maternal behavior ,   Motor phenotype ,   Neuroanatomy / Ultrastructure / Cytoarchitecture ,   Repetitive behavior ,   Seizure ,   Sensory ,   Social behavior ,  

NLGN3_3_KI_R451C

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Size /growth1
Abnormal
Description: Abnormal size/growth.
Exp Paradigm: General Observation
 General Observation
 Unreported
Ultrasonic vocalization1
Abnormal
Description: Abnormal Ultrasonic Vocalization
Exp Paradigm: Maternal separation
 Maternal separation
 Postnatal day 8
Other1
Abnormal
Description: Abnormal motor phenotype
Exp Paradigm: Accelerating rota rod test
 Accelerating rota rod test
 Adult; Males
righting response1
Abnormal
Description: Abnormal righting response
 
 Postnatal day 2-6
Other1
Abnormal
Description: Abnormal motor phenotype
 
 
hearing1
Abnormal
Description: Abnormal hearing
 
 
Other1
Abnormal
Description: Abnormal sensory
Exp Paradigm: Homing test
 Homing test
 Postnatal day 9, Females
 No Change
 
 
 No Change
 
 
 No Change
 
 
 Not Reported: Circadian sleep/wake cycle ,   Homeostasis ,   Immune response ,   Maternal behavior ,   Molecular profile ,   Neuroanatomy / Ultrastructure / Cytoarchitecture ,   Neurophysiology ,   Repetitive behavior ,   Seizure ,  



Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
AES amino-terminal enhancer of split 166 Q08117 Y2H
Sakai Y 2011
AKT1 v-akt murine thymoma viral oncogene homolog 1 207 P31749 Y2H
Sakai Y 2011
APC2 adenomatosis polyposis coli 2 10297 O95996 Y2H
Sakai Y 2011
ATXN1 ataxin 1 6310 P54253 Y2H
Sakai Y 2011
COBL cordon-bleu homolog (mouse) 23242 O75128 Y2H
Sakai Y 2011
EFEMP1 EGF containing fibulin-like extracellular matrix protein 1 2202 Q12805 Y2H
Sakai Y 2011
HIVEP1 human immunodeficiency virus type I enhancer binding protein 1 3096 P15822 Y2H
Sakai Y 2011
PICK1 protein interacting with PRKCA 1 9463 Q9NRD5 Y2H
Sakai Y 2011
RBFOX1 RNA binding protein, fox-1 homolog (C. elegans) 1 54715 Q9NWB1 in silico target prediction/splicing microarray
Zhang C 2008
TDRD7 tudor domain containing 7 23424 Q8NHU6 Y2H
Sakai Y 2011
Nlgn1 neuroligin 1 192167 Q99K10 IP/WB (mouse brain)
Budreck EC 2007
Nlgn2 neuroligin 2 216856 Q69ZK9 IP/WB (mouse brain)
Budreck EC 2007
Dlg2 discs, large homolog 2 (Drosophila) 64053 Q63622 Y2H
Irie M 1997
Dlg3 discs, large homolog 3 (Drosophila) 58948 Q62936 Y2H
Irie M 1997
Dlg4 discs, large homolog 4 (Drosophila) 29495 P31016 affinity chromatography (rat brain)
Y2H
Irie M 1997
Nrxn1 neurexin 1 60391 Q63373 IP/WB (rat brain)
Ichtchenko K 1996
Nrxn2 neurexin 2 116595 Q63376 IP/WB (rat brain)
Ichtchenko K 1996
Nrxn3 neurexin 3 116508 N/A IP/WB (rat brain)
Ichtchenko K 1996
Rapgef4 Rap guanine nucleotide exchange factor (GEF) 4 252857 Q9Z1C7 IP/WB (rat brain)
Woolfrey KM 2009

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