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Relevance to Autism

Several studies have found rare variants in the NLGN4X gene in autism. Association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts).

Molecular Function

Neuroligins are cell-adhesion molecules at the postsynaptic side of the synapse .

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
Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.
ASD
Positive Association
Analysis of four neuroligin genes as candidates for autism.
ASD
Positive association
Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.
ASD
Positive Association
A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population.
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
Support
Familial deletion within NLGN4 associated with autism and Tourette syndrome.
ASD
TS
Support
Using whole-exome sequencing to identify inherited causes of autism.
ASD
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
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
Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies.
DD, ID
ASD, ADHD
Support
Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.
ASD
MR
Recent Recommendation
The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.
Recent Recommendation
A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.
Recent Recommendation
Unusually rapid evolution of Neuroligin-4 in mice.
Recent Recommendation
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
Recent Recommendation
Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN172R001 
 Insertion 
 1186insT 
 stop 396 
  
  
  
 GEN172R002 
 Missense 
 A1597G 
 K378R 
 Familial 
 Maternal 
  
 GEN172R003 
 Silent 
 C1397T 
 N/A 
  
  
  
 GEN172R004 
 Silent 
 C1310T 
 N/A 
  
  
  
 GEN172R005 
 Silent 
 C1805T 
 N/A 
  
  
  
 GEN172R006 
 Silent 
 C2241TC2243G 
 N/A 
  
  
  
 GEN172R007 
 Substitution 
 G-335A 
 N/A 
 De novo 
  
  
 GEN172R008 
 Deletion 
 N/A 
 N/A 
 Familial 
 Maternal 
 Multiplex 
 GEN172R009 
 Duplication 
  
  
 Familial 
 Maternal 
  
 GEN172R010 
 Coding-synonymous 
 c.297C>T 
 G99G 
 Unknown 
  
 Unknown 
 GEN172R011 
 Coding-synonymous 
 c.516C>T 
 I172I 
 Unknown 
  
 Unknown 
 GEN172R012 
 Coding-synonymous 
 c.1590C>T 
 F530F 
 Unknown 
  
 Unknown 
 GEN172R013 
 Substitution 
 A>G 
 3'UTR 
 Familial 
 Maternal 
 Multiplex 
 GEN172R014 
 Deletion 
 del(2) 
 3'UTR 
 Familial 
 Maternal 
 Multiplex 
 GEN172R015 
 Duplication 
  
  
 Unknown 
  
 Unknown 
 GEN172R016 
 Nonsense 
 c.985C>T 
 Q329X 
 Familial 
 Maternal 
 Simplex 
 GEN172R017 
 Missense 
 c.2297G>A 
 R766Q 
 Familial 
 Maternal 
 Simplex 
 GEN172R018 
 Missense 
 c.250G>A 
 G84R 
 Familial 
 Maternal 
 Simplex 
 GEN172R019 
 Missense 
 c.484C>A 
 Q162K 
 De novo 
  
 Simplex 
 GEN172R020 
 Missense 
 c.847G>A 
 A283T 
 Familial 
 Maternal 
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN172C001 
  
 DXS996 
 N/A 
 N/A 
 Finnish 
 Replication 
 GEN172C002 
 Substitution 
 rs12836764 
 N/A 
 N/A 
 Caucasian 
 Replication 
 GEN172C003 
 Silent 
 rs3747333 
 N/A 
 N/A 
 Quebec 
 Replication 
 GEN172C004 
 Silent 
 rs3747334 
 N/A 
 N/A 
 Quebec 
 Replication 
 GEN172C005 
 Substitution 
 rs2290487 
 G to A 
 N/A 
 IMGSAC 
 Replication 
 GEN172C006 
 Substitution 
 rs2290488 
 G34C 
 N/A 
 IMGSAC 
 Replication 
 GEN172C007 
 Silent 
 rs7049300 
 C1397T 
 N/A 
 IMGSAC 
 Replication 
 GEN172C008 
 Silent 
 rs3747333, rs3747334 
 C2241TC2243G 
 N/A 
 IMGSAC 
 Replication 
 GEN172C009 
 Missense 
 rs3747333 
 C/T 
  
 318 Chinese ASD cases, 453 Chinese controls 
  
 GEN172C010 
 Coding-synonymous 
 rs3747334 
 C/G 
  
 319 Chinese ASD cases, 453 Chinese controls 
  



Model Summary

Selective deficit in reciprocal social interaction and communication modeling ASD

External Links

AllenBrainAtlas   MGI Logo  Entrez Gene

References

Type
Title
Author, Year
Primary
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
Additional
Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.

NLGN4X_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene trap vector inserted 340 bp downstream of the first exon. The resulting chimeric protein is nonfunctional, encoding residues 1138, in-frame with beta-galactosidase sequence.
Allele Type: Gene trapped
Strain of Origin: 129P2/OlaHsd
Genetic Background: B6.129P2
ES Cell Line: Not Specified
Mutant ES Cell Line: XST093
Model Source: BayGenomics

NLGN4X_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene trap insertion 340 bp downstream of the first exon of Nlgn4 creating a null mutation
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

NLGN4X_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Gene trap insertion 340 bp downstream of the first exon of Nlgn4 creating a null mutation
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

NLGN4X_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Brain size1
Decreased
Description: Reduced Brain Size
Exp Paradigm: MRI Volumetry
 MRI Volumetry
 3 months
Aggression1
Abnormal
Description: Abnormal Aggression
Exp Paradigm: Resident Intruder test
 Resident Intruder test
 3 months
Social Approach1
Abnormal
Description: Abnormal Social Approach.
Exp Paradigm: Social preference test in tripartite chamber.
 Social preference test in tripartite chamber.
 3 months
Social Interaction1
Decreased
Description: Reduced Social Interaction
Exp Paradigm: Direct contacts between genetically identical pairs test.
 Direct contact test
 3 months
Aggression1
Abnormal
Description: Abnormal Aggression
Exp Paradigm: Modified Resident Intruder test
 Modified Resident Intruder test
 3 months
Ultrasonic Vocalization1
Decreased
Description: Reduced Ultrasonic Vocalization
Exp Paradigm: Call latency towards unfamiliar female mouse in estrous.
 Call latency towards unfamiliar female mouse in estrous.
 3 months
General Characteristics1
 No Change
 Viability and fertility
 3 months
Anxiety1
 No Change
 Elevated plus maze test
 3 months
Anxiety1
 No Change
 Open field test.
 3 months
Exploratory activity1
 No Change
 Holeboard test.
 3 months
General Curiosity1
 No Change
 Object preference test.
 3 months
Cognitive Flexibility1
 No Change
 Reversal training
 3 months
Cued conditioning anomalies1
 No Change
 Cued and contextual fear conditioning.
 3 months
Spatial Learning1
 No Change
 Hidden platform test
 3 months
Muscle Coordination1
 No Change
 Rota-rod test
 3 months
Seizure1
 No Change
 
 3 months
Hearing1
 No Change
 Startle response test
 3 months
Olfaction1
 No Change
 Buried food finding test.
 3 months
Sensorimotor gating1
 No Change
 Acoustic startle response
 3 months
Taste1
 No Change
 Sucrose preference test.
 3 months
Vision1
 No Change
 Visible platform test
 3 months
 Not Reported: Circadian sleep/wake cycle ,   Homeostasis ,   Immune response ,   Maternal behavior ,   Molecular profile ,   Neurophysiology ,   Repetitive behavior ,  

NLGN4X_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Size/Weight1
Developmental Trajectory
Description: No change in developmental trajectory indicated by normal neurological reflex, motor function, response to handling and no bald patches
Exp Paradigm: General Observations
 General Observations
 
General Locomotor Activity1
29
Description: No change in locomotor activity as measured by total distance traveled and time spent in center zone
Exp Paradigm: Open field test
 Open field test
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Developmental Milestone1
 No Change
 General Observations
 PD2-14
Size/Weight1
 No Change
 General Observations
 10-16 weeks
Anxiety1
 No Change
 Elevated plus maze test
 
Exploratory activity1
 No Change
 Reciprocal social interaction
 PD 21-24
Motor coordination1
 No Change
 Rotarod test
 
Pain1
 No change
 Tail flick; Hot plate test
 
Aggression1
 No Change
 
 
Self Grooming1
 No Change
 Reciprocal social interaction
 PD 21-24
Sociability1
 No Change
 Automated three-chambered task
 
Social Interaction1
 No Change
 Male-female social interaction test
 
Social Interaction1
 No Change
 Reciprocal social interaction
 PD 21-24
 Not Reported: Circadian sleep/wake cycle ,   Homeostasis ,   Immune response ,   Maternal behavior ,   Molecular Profile ,   Neuroanatomy / Ultrastructure / Cytoarchitecture ,   Neurophysiology ,   Repetitive behavior ,   Seizure ,  

NLGN4X_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Size/Weight1
Developmental Trajectory
Description: No change in developmental trajectory indicated by normal neurological reflex, motor function, response to handling and no bald patches
Exp Paradigm: General Observations
 General Observations
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Ultrasonic Vocalization1
 No Change
 Ultrasonic vocalizations measurements
 
Developmental Milestone1
 No Change
 General Observations
 PD2-14
Size/Weight1
 No Change
 General Observations
 10-16 weeks
Anxiety1
 No Change
 Elevated plus maze test
 
Exploratory activity1
 No Change
 Reciprocal social interaction
 PD 21-24
General Locomotor Activity1
 No Change
 Open field test
 
Motor coordination1
 No Change
 Rotarod test
 
Pain1
 No change
 Tail flick; Hot plate test
 
Aggression1
 No Change
 
 
Self Grooming1
 No Change
 Reciprocal social interaction
 PD 21-24
Sociability1
 No Change
 Automated three-chambered task
 
Social Interaction1
 No Change
 Male-female social interaction test
 
Social Interaction1
 No Change
 Reciprocal social interaction
 PD 21-24
 Not Reported: Circadian sleep/wake cycle ,   Homeostasis ,   Immune response ,   Learning & memory ,   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
DLG4 DLG4?discs, large homolog 4 (Drosophila) 1742 P78352 IP/WB (COS-7 cells)
Bolliger MF 2001
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP (HEK293 cells)
Ascano M Jr 2012
SNTG2 syntrophin, gamma 2 54221 Q9NY99 IP/WB (COS-7 cells)
Y2H
Yamakawa H 2007

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