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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
Integrating de novo and inherited variants in 42
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
ASD, DD, ID
Support
Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort
DD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
ID
Stereotypic behavior
Support
Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders
DD
Support
Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders
DD, ID
Epilepsy/seizures
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
ASD
DD, ID, epilepsy/seizures
Support
Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing.
ASD
Support
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
Support
ASD, epilepsy/seizures
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Recent Recommendation
Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.
Recent Recommendation
Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN271R001 
 frameshift_variant 
 c.2734del 
 p.Leu912CysfsTer76 
 Familial 
 Paternal 
 Simplex 
 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.2442G>A 
 p.Ala814= 
 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.Gly271ArgfsTer26 
 De novo 
  
 Simplex 
 GEN271R019 
 frameshift_variant 
 c.3651del 
 p.Asn1217LysfsTer3 
 Familial 
 Paternal 
 Multiplex 
 GEN271R020 
 frameshift_variant 
 c.4253-512del 
  
 De novo 
  
 Simplex 
 GEN271R021 
 missense_variant 
 c.876C>G 
 p.Phe292Leu 
 De novo 
  
 Simplex 
 GEN271R022 
 synonymous_variant 
 c.4189C>T 
 p.Leu1397%3D 
 De novo 
  
 Multiplex 
 GEN271R023 
 missense_variant 
 c.3526G>A 
 p.Ala1176Thr 
 De novo 
  
 Simplex 
 GEN271R024 
 synonymous_variant 
 c.1500C>T 
 p.Pro500%3D 
 De novo 
  
  
 GEN271R025 
 missense_variant 
 c.1600C>A 
 p.Gln534Lys 
 Unknown 
  
  
 GEN271R026 
 missense_variant 
 c.797C>T 
 p.Ser266Phe 
 Familial 
 Maternal 
  
 GEN271R027 
 missense_variant 
 c.1799G>T 
 p.Gly600Val 
 Familial 
 Maternal 
 Simplex 
 GEN271R028 
 frameshift_variant 
 c.808dup 
 p.Ala270GlyfsTer27 
 Familial 
 Maternal 
  
 GEN271R029 
 frameshift_variant 
 c.808dup 
 p.Ala270GlyfsTer27 
 Familial 
 Paternal 
  
 GEN271R030 
 missense_variant 
 c.1901G>T 
 p.Gly634Val 
 Familial 
 Maternal 
  
 GEN271R031 
 missense_variant 
 c.4296C>A 
 p.Asp1432Glu 
 Unknown 
  
  
 GEN271R032 
 missense_variant 
 c.1108G>A 
 p.Asp370Asn 
 Unknown 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Deletion
 13
 

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.
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:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity2
Decreased
 Open field test
 10 weeks
Presynaptic function: paired-pulse facilitation2
Decreased
 Paired-pulse ratio
 P14-p21
Miniature post synaptic current frequency: excitatory2
Decreased
 Whole-cell patch clamp
 P14-p21
Decay kinetics of evoked post synaptic currents2
Increased
 Whole-cell patch clamp
 P14-p21
Synaptic transmission: excitatory2
Decreased
 Whole-cell patch clamp
 P14-p21
Self grooming: perseveration2
Increased
 Grooming behavior assessments
 10 weeks
Social approach2
Decreased
 Three-chamber social approach test
 10 weeks
Social memory1
Decreased
 Three-chamber social approach test
 >8 weeks
Nest building behavior2
Decreased
 Nest building assay
 10 weeks
Social interaction2
Decreased
 Reciprocal social interaction test
 10 weeks
Social approach1
Decreased
 Three-chamber social approach test
 >8 weeks
Anxiety1
Increased
 Light-dark exploration test
 >8 weeks
Anxiety2
Increased
 Light-dark exploration test
 10 weeks
Anxiety1
Increased
 Elevated plus maze test
 >8 weeks
Anxiety2
Increased
 Elevated plus maze test
 10 weeks
Anxiety1
Increased
 Open field test
 >8 weeks
Object recognition memory2
Decreased
 Novel object recognition test
 >8 weeks
Protein expression level evidence1
Decreased
 Western blot
 NA
Gene expression1
Decreased
 Quantitative pcr (qrt-pcr)
 NA
Anxiety2
 No change
 Open field test
 10 weeks
Depression1
 No change
 Forced swim test
 >8 weeks
Depression1
 No change
 Tail suspension test
 >8 weeks
Cued or contextual fear conditioning: passive avoidance1
 No change
 Passive avoidance test
 >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
 10 weeks
Protein expression level evidence1
 No change
 Western blot
 NA
General locomotor activity2
 No change
 Open field test
 >8 weeks
General locomotor activity2
 No change
 Elevated plus maze test
 10 weeks
General locomotor activity2
 No change
 Light-dark exploration 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
 NA
 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
 NA
 P14-p21
Self grooming: perseveration1
 No change
 Open field test
 >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, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Seizure





Download NRXN2's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
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
MAPK6 mitogen-activated protein kinase 6 5597 Q16659 Y2H
Vinayagam A , et al. 2011
MIB1 mindbomb E3 ubiquitin protein ligase 1 307594 D3ZUV2 Affinity chromatography; LC-MS/MS
Mertz J , et al. 2015
NLGN1 neuroligin 1 192167 Q99K10 IP/WB
Singh SK , et al. 2016
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
Sdcbp syndecan binding protein 53378 O08992 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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