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Relevance to Autism

Rare mutations in the NRXN2 gene have been identified with ASD (Gauthier et al., 2011).

Molecular Function

This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.
ASD
Positive Association
Neurexin gene family variants as risk factors for autism spectrum disorder.
ASD
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
ID
Stereotypic behavior
Support
Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.
ASD
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing.
ASD
Support
A de novo 921Kb microdeletion at 11q13.1 including neurexin 2 in a boy with developmental delay, deficits in speech and language without autistic ...
DD, absent speech
Recent Recommendation
Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.
Recent Recommendation
Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN271R001 
 frameshift_variant 
 c.2733delT 
 p.Pro911fs 
 Familial 
 Paternal 
 Multi-generational 
 GEN271R002 
 missense_variant 
 c.598G>A 
 p.Ala200Thr 
 Familial 
  
  
 GEN271R003 
 missense_variant 
 c.803G>T 
 p.Gly268Val 
 Familial 
  
  
 GEN271R004 
 missense_variant 
 c.1888G>A 
 p.Gly630Ser 
 Familial 
  
  
 GEN271R005 
 missense_variant 
 c.1964T>C 
 p.Val655Ala 
 Familial 
  
  
 GEN271R006 
 missense_variant 
 c.2413C>T 
 p.Pro805Ser 
 Familial 
  
  
 GEN271R007 
 missense_variant 
 c.2441C>T 
 p.Ala814Val 
 Familial 
  
  
 GEN271R008 
 missense_variant 
 c.3091C>G 
 p.Arg1031Gly 
 Familial 
  
  
 GEN271R009 
 missense_variant 
 c.3241G>A 
 p.Asp1081Asn 
 Familial 
  
  
 GEN271R010 
 missense_variant 
 c.3250C>T 
 p.His1084Tyr 
 Familial 
  
  
 GEN271R011 
 missense_variant 
 c.5087C>A 
 p.Pro1696His 
 Familial 
  
  
 GEN271R012 
 missense_variant 
 c.1090G>A 
 p.Val364Ile 
 Familial 
  
 Extended multiplex (at least one pair of ASD affec 
 GEN271R013 
 missense_variant 
 c.1814G>A 
 p.Arg605Gln 
 De novo 
  
 Simplex 
 GEN271R014 
 synonymous_variant 
 C>T 
 p.(=) 
 De novo 
  
 Simplex 
 GEN271R015 
 missense_variant 
 c.1795G>A 
 p.Gly599Ser 
 Familial 
  
 Simplex 
 GEN271R016 
 missense_variant 
 c.2904G>C 
 p.Arg968Ser 
 Familial 
  
 Simplex 
 GEN271R017 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN271R018 
 frameshift_variant 
 c.809_810insG 
 p.Ala270fs 
 De novo 
  
 Simplex 
 GEN271R019 
 frameshift_variant 
 delT 
  
 Familial 
 Paternal 
 Multiplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN271C001 
 missense_variant 
 rs12273892 
 c.242T>A 
 p.Leu81Gln 
 529 Chinese ASD cases (441 male, 63 female, 25 without gender information; mean age, 8.24 3.16 years) and 1923 healthy Chinese controls (1683 male, 240 fermale; mean age, 61.38 8.51 years) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion
 11
 

Model Summary

Neurexin null mice have deficiencies is social interaction and display increased anxiety in some behavioral tasks. Increased repetitive behavior has been noted in females only, indicating some sexually dimorphic phenotypes.

References

Type
Title
Author, Year
Primary
Deletion of -neurexin II results in autism-related behaviors in mice.
Additional
Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.

M_Nrxn2_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A neo cassette replaces the first exon of the Nrxn2 gene that contains the complete 5' UTR, start codon, signal peptide and the first LNS domain. Mice were backcrossed for 8 generations on to the C57BL/6NCrl background.
Allele Type: Targeted(Knockout)
Strain of Origin: 129
Genetic Background: C57BL/6NCrl or C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_Nrxn2_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: To delete both alpha and beta forms of neurexin2 part of exon# 23 was deleted and the gene was interrupted between splice insert #5 in the 3' UTR, mice were maintained in the C57BL/6J background.
Allele Type: Targeted(Knockout)
Strain of Origin: 129
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source: Sudhof laboratory

M_Nrxn2_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: A neo cassette replaces the first exon of the Nrxn2 gene that contains the complete 5' UTR, start codon, signal peptide and the first LNS domain. Mice were backcrossed for 8 generations on to the C57BL/6J background.
Allele Type: Targeted(Knockout)
Strain of Origin: 129
Genetic Background: C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_Nrxn2_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity2
Decreased
Description: General locomotor activity is reduced in the Nrxn2 null mice in the open field test
 Open field test
 10 weeks
Miniature post synaptic current frequency: excitatory2
Decreased
Description: The excitatory synapses have reduced frequency of miniature post-synaptic excitatory currents in Nrxn2 null mice
 Whole-cell patch clamp
 P14-P21
Decay kinetics of evoked post synaptic currents2
Increased
Description: The time constants for decay were significantly increased in evoked post synaptic excitatory currents, leading to faster decay of currents
 Whole-cell patch clamp
 P14-P21
Synaptic transmission: excitatory2
Decreased
Description: There is a significant reduction in NMDAR mediated post synaptic currents in the NRXN2 null mice
 Whole-cell patch clamp
 P14-P21
Presynaptic function: paired-pulse facilitation2
Decreased
Description: Excitatory synapses have no (absent) paired pulse facilitation in the Nrxn2 complete KO mice (2 alpha and beta)
 Paired-pulse ratio:
 P14-P21
Self grooming: perseveration2
Increased
Description: Only female Nrxn2 null mice show increased self grooming compared to female wild type controls. Male null mice do not show an increase in self grooming compared to controls
 Grooming behavior assessments
 10 weeks
Social interaction2
Decreased
Description: Female Nrxn2 null mice have low levels of social interaction in the reciprocal social interaction test. Males perform similar to male control mice
Exp Paradigm: Females only
 Reciprocal social interaction test
 10 weeks
Social approach1
Decreased
Description: Nrxn2 null mice show reduced preference to unfamiliar stimulus mouse over an empty cage in the three-chambered social approach test
 Three-chamber social approach test
 >8 weeks
Social approach2
Decreased
Description: Female Nrxn2 null mice have reduced social approach or sociability indicated by low preference for an unfamiliar mouse in the three chamber social approach test. Male Nrxn2 null mice have similar sociability as wild type controls
Exp Paradigm: Females only
 Three-chamber social approach test
 10 weeks
Social memory1
Decreased
Description: Nrxn2 null mice show no preference for new unfamiliar stimulus mouse over a familiar mouse
 Three-chamber social approach test
 >8 weeks
Nest building behavior2
Decreased
Description: Both male and female Nrxn2 null mice have reduced nesting material in their nests compared to wild type controls.
 Nest building assay
 10 weeks
Anxiety1
Increased
Description: Nrxn2 mice spend more time in the periphery of the open field compared to the control mice, take longer to cross over to from dark to light and also spend less time in the open arms of the elevated plus maze
Exp Paradigm: Light-dark exploration test
 Light-dark exploration test: Light-dark exploration test
 >8 weeks
Anxiety1
Increased
Description: Nrxn2 mice spend more time in the periphery of the open field compared to the control mice, take longer to cross over to from dark to light and also spend less time in the open arms of the elevated plus maze
Exp Paradigm:  Open field test
 Open field test
 >8 weeks
Anxiety2
Increased
Description: Nrxn2 null mice show increased anxiety levels in the light/dark box test and in the elevated plus maze
Exp Paradigm: Elevated plus maze test
 Elevated plus maze test
 10 weeks
Anxiety1
Increased
Description: Nrxn2 mice spend more time in the periphery of the open field compared to the control mice, take longer to cross over to from dark to light and also spend less time in the open arms of the elevated plus maze
Exp Paradigm:  Elevated plus maze test
 Elevated plus maze test
 >8 weeks
Anxiety2
Increased
Description: Nrxn2 null mice show increased anxiety levels in the light/dark box test and in the elevated plus maze
Exp Paradigm:  Light-dark exploration test
 Light-dark exploration test: Light-dark exploration test
 10 weeks
Object recognition memory2
Decreased
Description: Nrxn2 null mice have reduced object recognition memory as they spend less time exploring a novel object compared to littermate controls
 Novel object recognition test
 >8 weeks
Gene expression1
Decreased
Description: There is significantly reduced expression of Dlg4, Parvalbumin, Grin2a and Stxbp1 in the hippocampus. Dlg4 transcript levels were reduced in both the hippocampus and frontal cortex
 Quantitative PCR (qRT-PCR): mRNA levels measured in the frontal cortex and hippocampus
 
Protein expression level evidence1
Decreased
Description: Munc18-1 protein levels were reduced in the Nrxn2 null mice hippocampus, this is the protein product of the Stxbp1 gene
 Western blot
 
Anxiety2
 No Change
 Open field test
 10 weeks
Depression1
 No Change
 Tail suspension test
 >8 weeks
Depression1
 No Change
 Forced swim test
 >8 weeks
Cued or contextual fear conditioning: Passive avoidance1
 No Change
 Passive avoidance test: step through passive avoidance
 >8 weeks
Spatial learning2
 No Change
 Morris water maze test
 10 weeks
Spatial reference memory2
 No Change
 Morris water maze test
 10 weeks
Spatial working memory2
 No Change
 Morris water maze test: delayed matching to place
 10 weeks
Protein expression level evidence1
 No Change
 Western blot
 
General locomotor activity2
 No Change
 Open field test
 >8 weeks
General locomotor activity2
 No Change
 Light-dark exploration test: Light-dark exploration test
 10 weeks
General locomotor activity2
 No Change
 Elevated plus maze test
 10 weeks
General locomotor activity: Ambulatory activity1
 No Change
 Open field test
 >8 weeks
Synapse density: Excitatory2
 No Change
 Electron microscopy
 P14-P21
Synaptic morphology2
 No Change
 
 P14-P21
Decay kinetics of miniature post synaptic currents2
 No Change
 Whole-cell patch clamp
 P14-P21
Miniature post synaptic current amplitude: excitatory2
 No Change
 Whole-cell patch clamp
 P14-P21
Neurotransmitter release: quantal parameters2
 No Change
 
 P14-P21
Self grooming: perseveration1
 No Change
 Open field test: grooming observations
 >8 weeks
Olfaction2
 No Change
 Buried food test
 10 weeks
Olfaction1
 No Change
 Buried food test
 >8 weeks
Sensorimotor gating1
 No Change
 Prepulse inhibition
 >8 weeks
Startle response: acoustic stimulus1
 No Change
 Acoustic startle reflex test
 >8 weeks
Social memory2
 No Change
 Three-chamber social approach test
 10 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure

M_Nrxn2_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Miniature post synaptic current amplitude: excitatory1
Decreased
Description: The excitatory synapses have reduced amplitude of miniature post-synaptic excitatory currents in Nrxn2 null mice
 Whole-cell patch clamp
 P14-P21
Decay kinetics of evoked post synaptic currents1
Increased
Description: The time constants for decay were significantly increased in evoked post synaptic excitatory currents, leading to faster decay of currents
 Whole-cell patch clamp
 P14-P21
Synaptic transmission: excitatory1
Decreased
Description: There is a significant reduction in NMDAR mediated post synaptic currents in the NRXN2 null mice
 Whole-cell patch clamp
 P14-P21
Presynaptic function: paired-pulse facilitation1
Decreased
Description: Excitatory synapses show significantly reduced paired pulse facilitation
 Paired-pulse ratio:
 P14-P21
Size/growth1
Decreased
Description: Nrxn2 complete null mice have growth retardation
 
 
Synapse density: Excitatory1
 No Change
 Electron microscopy
 P14-P21
Synapse density: Inhibitory1
 No Change
 Electron microscopy
 P14-P21
Synaptic morphology1
 No Change
 Electron microscopy
 P14-P21
Decay kinetics of miniature post synaptic currents1
 No Change
 Whole-cell patch clamp
 P14-P21
Intrinsic membrane properties1
 No Change
 Whole-cell patch clamp
 P14-P21
Miniature post synaptic current frequency: excitatory1
 No Change
 Whole-cell patch clamp
 P14-P21
Miniature post synaptic currents: inhibitory1
 No Change
 Whole-cell patch clamp
 P14-P21
Neurotransmitter release: quantal parameters1
 No Change
 
 P14-P21
Presynaptic function: paired-pulse facilitation1
 No Change
 Whole-cell patch clamp
 P14-P21
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Repetitive behavior, Seizure, Sensory, Social behavior

M_Nrxn2_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Anxiety1
 No Change
 Elevated plus maze test
 10 weeks
Anxiety1
 No Change
 Light-dark exploration test: Light-dark exploration test
 10 weeks
Anxiety1
 No Change
 Open field test
 10 weeks
Spatial learning1
 No Change
 Morris water maze test
 10 weeks
Spatial reference memory1
 No Change
 Morris water maze test
 10 weeks
Spatial working memory1
 No Change
 Morris water maze test: delayed matching to place
 10 weeks
General locomotor activity1
 No Change
 Elevated plus maze test
 10 weeks
General locomotor activity1
 No Change
 Open field test
 10 weeks
Self grooming: perseveration1
 No Change
 Grooming behavior assessments
 10 weeks
Social approach1
 No Change
 Three-chamber social approach test
 10 weeks
Social interaction1
 No Change
 Reciprocal social interaction test
 10 weeks
Social memory1
 No Change
 Three-chamber social approach test
 10 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
MAPK6 mitogen-activated protein kinase 6 5597 Q16659 Y2H
Vinayagam A , et al. 2011
Cask calcium/calmodulin-dependent serine protein kinase (MAGUK family) 12361 O70589 IP; LC-MS/MS
Muhammad K , et al. 2015
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
GRID2 glutamate receptor, ionotropic, delta 2 14804 Q61625 IP; LC-MS/MS; Cell surface binding assay; Cell aggregation assay
Uemura T , et al. 2010
Khdrbs3 KH domain containing, RNA binding, signal transduction associated 3 13992 Q9R226 RNA-Seq; RT-PCR
Traunmller L , et al. 2016
NLGN1 neuroligin 1 192167 Q99K10 IP/WB
Singh SK , et al. 2016
Sdcbp syndecan binding protein 53378 O08992 IP; LC-MS/MS
Muhammad K , et al. 2015
MIB1 mindbomb E3 ubiquitin protein ligase 1 307594 D3ZUV2 Affinity chromatography; LC-MS/MS
Mertz J , et al. 2015
NLGN1 neuroligin 1 116647 Q62765 IP/WB
Ichtchenko K , et al. 1996
NLGN3 neuroligin 3 171297 Q62889 IP/WB
Ichtchenko K , et al. 1996
Ppp1r9b protein phosphatase 1, regulatory subunit 9B 84686 O35274 IP; LC-MS/MS
Muhammad K , et al. 2015
Sorcs1 sortilin-related VPS10 domain containing receptor 1 309533 F1LUZ4 IP; LC-MS/MS
Savas JN , et al. 2015

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