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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
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
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
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
Negative Association
Analysis of the SNP rs3747333 and rs3747334 in NLGN4X gene in autism spectrum disorder: a meta-analysis.
ASD
Negative Association
Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation.
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
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
ID, epilepsy/seizures
Support
Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.
ASD
Support
Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.
ASD
Support
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
TS
Support
Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect...
ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...
DD, ID
ASD, ADHD
Support
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.
ID
Autistic behavior
Support
A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.
ASD
Support
GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil...
ASD, ID
Support
Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.
ASD
MR
Support
Using whole-exome sequencing to identify inherited causes of autism.
ASD
Support
Familial deletion within NLGN4 associated with autism and Tourette syndrome.
ASD
TS
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Highly Cited
X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.
ID
ASD
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Recent Recommendation
The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.
Recent Recommendation
Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms
ASD
Recent Recommendation
Unusually rapid evolution of Neuroligin-4 in mice.
Recent Recommendation
A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y
ASD, ID
Recent Recommendation
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
Recent Recommendation
Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.
Recent Recommendation
Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.
Recent Recommendation
Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.
Recent Recommendation
Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN172R001 
 frameshift_variant 
 c.1186_1187insT 
 p.Asp396ValfsTer16 
  
  
  
 GEN172R002 
 missense_variant 
 c.1133A>G 
 p.Lys378Arg 
 Familial 
 Maternal 
  
 GEN172R003 
 synonymous_variant 
 c.1397C>T 
 p.Pro466Leu 
  
  
  
 GEN172R004 
 synonymous_variant 
 c.1310G>A 
 p.Arg437Gln 
  
  
  
 GEN172R005 
 synonymous_variant 
 c.1805C>T 
 p.(=) 
  
  
  
 GEN172R006 
 synonymous_variant 
 C2241TC2243G 
 p.(=) 
  
  
  
 GEN172R007 
 2KB_upstream_variant 
 c.-335G>A 
  
 De novo 
 NA 
 Simplex 
 GEN172R008 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R009 
 copy_number_gain 
  
  
 Familial 
 Maternal 
  
 GEN172R010 
 synonymous_variant 
 c.297C>T 
 p.Gly99= 
 Unknown 
  
 Unknown 
 GEN172R011 
 synonymous_variant 
 c.516C>T 
 p.Ile172= 
 Unknown 
  
 Unknown 
 GEN172R012 
 synonymous_variant 
 c.1590C>T 
 p.Phe530= 
 Unknown 
  
 Unknown 
 GEN172R013 
 3_prime_UTR_variant 
 c.1601+2982T>C 
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R014 
 3_prime_UTR_variant 
 c.1601+969del 
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R015 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN172R016 
 stop_gained 
 c.985C>T 
 p.Gln329Ter 
 Familial 
 Maternal 
 Simplex 
 GEN172R017 
 missense_variant 
 c.2297G>A 
 p.Arg766Gln 
 Familial 
 Maternal 
 Simplex 
 GEN172R018 
 missense_variant 
 c.250G>A 
 p.Gly84Arg 
 Familial 
 Maternal 
 Simplex 
 GEN172R019 
 missense_variant 
 c.484C>A 
 p.Gln162Lys 
 De novo 
 NA 
 Simplex 
 GEN172R020 
 missense_variant 
 c.847G>A 
 p.Ala283Thr 
 Familial 
 Maternal 
 Simplex 
 GEN172R021 
 missense_variant 
 c.392A>G 
 p.Asn131Ser 
 Unknown 
  
 Unknown 
 GEN172R022 
 missense_variant 
 c.295G>A 
 p.Gly99Ser 
 Familial 
 Maternal 
 Multiplex 
 GEN172R023 
 missense_variant 
 c.1133A>G 
 p.Lys378Arg 
 Familial 
 Maternal 
 Simplex 
 GEN172R024 
 missense_variant 
 c.1207G>A 
 p.Val403Met 
 Familial 
 Maternal 
 Multiplex 
 GEN172R025 
 missense_variant 
 c.2110C>T 
 p.Arg704Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN172R026 
 frameshift_variant 
 c.1254_1255del 
 p.Glu418AspfsTer12 
 Familial 
 Maternal 
 Multi-generational 
 GEN172R027 
 inframe_deletion 
 c.1361_1372del 
 p.Val454_Ala457del 
 De novo 
 NA 
  
 GEN172R028 
 stop_gained 
 c.820C>T 
 p.Gln274Ter 
 Familial 
 Maternal 
 Simplex 
 GEN172R029 
 frameshift_variant 
 c.632del 
 p.Leu211Ter 
 Unknown 
  
 Simplex 
 GEN172R030 
 missense_variant 
 c.1564G>A 
 p.Val522Met 
 De novo 
 NA 
 Simplex 
 GEN172R031 
 missense_variant 
 c.259C>T 
 p.Arg87Trp 
 De novo 
 NA 
 Multiplex 
 GEN172R032 
 missense_variant 
 c.281C>T 
 p.Pro94Leu 
 Unknown 
  
 Unknown 
 GEN172R033 
 missense_variant 
 c.302G>A 
 p.Arg101Gln 
 Familial 
 Maternal 
 Unknown 
 GEN172R034 
 missense_variant 
 c.325G>C 
 p.Val109Leu 
 Familial 
 Maternal 
 Unknown 
 GEN172R035 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN172R036 
 copy_number_loss 
  
  
 Unknown 
  
  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN172C001 
 intron_variant, microsatellite 
  
  
  
 Finnish 
 Discovery 
 GEN172C002 
 intron_variant 
 rs12836764 
 c.-306+6390T>C;c.-305-29322T>C;c.-306+5679T>C 
  
 Caucasian 
 Discovery 
 GEN172C003 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 Quebec 
 Discovery 
 GEN172C004 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 Quebec 
 Discovery 
 GEN172C005 
 intron_variant, 2KB_upstream_variant 
 rs2290487 
 c.-613+640G>A;c.-1327G>A;c.-518G>A;c.-306+640G>A;c.-1572G>A;c.-1341G>A;c.-2250G>A 
 G to A 
 IMGSAC 
 Discovery 
 GEN172C006 
 intron_variant, 2KB_upstream_variant, 5_prime_UTR_variant 
 rs2290488 
 c.-613+727G>C;c.-1240G>C;c.-431G>C;c.-306+727G>C;c.-1485G>C;c.-1254G>C;c.-2163G>C 
 G34C 
 IMGSAC 
 Discovery 
 GEN172C007 
 synonymous_variant 
 rs7049300 
 c.1397C>T;c.933C>T;c.993C>T 
 p.(=) 
 IMGSAC 
 Discovery 
 GEN172C008 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 IMGSAC 
 Discovery 
 GEN172C009 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 IMGSAC 
 Discovery 
 GEN172C010 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 318 Chinese ASD cases, 453 Chinese controls 
 Replication 
 GEN172C011 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 319 Chinese ASD cases, 453 Chinese controls 
 Replication 
 GEN172C012 
 intron_variant 
 rs12009217 
 c.625+26439T>C;c.685+26439T>C 
  
 40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 44
 
X
Deletion-Duplication
 10
 
X
Duplication
 2
 
X
Deletion-Duplication
 2
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 2
 
X
Deletion
 1
 
X
Duplication
 4
 
X
Deletion
 5
 
X
Duplication
 5
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

Model Summary

Nlg4 mutant flies show impairments in olfactory associative learning as well as a severe decrease in reversal learning task, a measure of behavioral flexibility. This deficit seems to be due to enhanced old memories, driven by inability to active Rac1-dependent forgetting. Nlg4-deficient mutant flies show decreased anxiety and altered sleep/activity patterns. Moreover, Nlg4 mutant flies show an increased probability to form groups which also are larger in size and less probability for males to remain single. When in groups, male Nlg4 mutants are more likely to form chains. When exposed to male courtship songs, mutant males are more like to show aggression towards other males.

References

Type
Title
Author, Year
Primary
Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes.
Primary
Neuroligins Nlg2 and Nlg4 Affect Social Behavior in Drosophila melanogaster.

F_NLG4_1_KO_HM_MB03367

Model Type: Genetic
Model Genotype: Homozygous
Mutation: .
Allele Type: Loss-of-function
Strain of Origin:
Genetic Background: w^1118
ES Cell Line:
Mutant ES Cell Line:
Model Source: Bloomington Drosophila Stock Center

F_NLG4_1_KO_HM_NLG4^DEL/LL01874

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Nlg4^del/LL01874 compound heterozygotes were generated by crossing an Nlg4^del deletion and an Nlg4 point mutation (Nlg4^LL01874) line. This strategy was adopted as each individual line leads to lethality in the homozygous state. .
Allele Type: Partial knockout
Strain of Origin: Unreported
Genetic Background: Canton S
ES Cell Line:
Mutant ES Cell Line:
Model Source: Junhai Han, Southeast University, Nanjing, China (PMID 24068821)

F_NLG4_1_KO_HM_MB03367

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Olfactory learning and memory1
Decreased
Description: Nlg4 mutants showed a decrease in olfactory associative aversive learning compared to controls.
 Olfactory classical conditioning
 Adult stage
Cued or contextual fear conditioning: memory of cue: long term recall1
Increased
Description: Nlg4 mutants showed an increase in olfactory associative aversive learning compared to controls.
 Olfactory classical conditioning
 Adult stage
Cognitive flexibility: associative learning1
Decreased
Description: Nlg4 mutants showed a severe decrease in olfactory reversal learning compared to controls.
 Reversal learning of olfactory classical conditioning
 Adult stage
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

F_NLG4_1_KO_HM_NLG4^DEL/LL01874

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle: dark phase1
Decreased
Description: Nlg4 mutant flies showed a decrease in locomotor activity during dark periods compared to controls.
Exp Paradigm: Locomotor activity measured in median beam crossings per hour for 10 hours around midnight.
 General observations
 5 7 days
Locomotor activity in diurnal cycle1
Decreased
Description: Nlg4 mutant flies showed a decrease in locomotor activity during light periods compared to controls.
Exp Paradigm: Locomotor activity measured in median beam crossings per hour for 10 hours around noon.
 General observations
 5 7 days
Circadian rhythms: timing/phases of locomotor activity1
Abnormal
Description: Nlg4 mutant flies showed altered sleep/activity patterns compared to controls. Specifically, Nlg4 mutants showed less frequent but longer sleep episodes compared to wild-type controls.
 General observations
 5 7 days
General locomotor activity1
Decreased
Description: Nlg4 mutant flies showed a decrease in overall locomotor activity compared to controls.
Exp Paradigm: Locomotor activity measured in median beam crossings
 Beam crossing
 5 7 days
Aggression: auditory stimulus induced1
Increased
Description: Nlg4 mutant fly males showed an increased aggression to other males in response to stimulation with courtship song stimulus compared to controls. Nlg4 mutant fly males showed no change in aggressive behavior towards other males in response to either white noise or aggression sound stimulus compared to controls.
Exp Paradigm: Courtship song stimulus (test stimulus); White noise or aggression sound stimulus (control stimuli)
 Competitive courtship assay
 7 12 days
Social cohesion1
Increased
Description: Nlg4 mutant flies showed an increased probability to form a group compared to controls. Specifically, Nlg4 mutants showed a decreased probability of remaining single (24%), an increase in preferred group size, and a decrease in distance to next neighbor compared to controls.
 Group behavior analysis
 5 7 days
Mating behavior: male courtship behavior: chaining1
Increased
Description: Nlg4 mutant flies showed a significant increase in male chaining behavior compared to controls.
 General observations
 5 7 days
Anxiety1
Decreased
Description: Nlg4 mutant flies showed decreased centrophobia (i.e., avoidance of open areas of an arena) compared to controls.
 General observations
 5 7 days
Targeted expression1
Decreased
Description: Nlg4 mutant flies showed reduced levels of Nlg2 transcript (40%) compared controls.
 Quantitative pcr (qrt-pcr)
 5 7 days
General locomotor activity1
 No change
 General observations
 5 7 days
Sensory-evoked response: excitation: auditory stimulus1
 No change
 Application of auditory stimuli
 5 7 days
Mating behavior: male courtship behavior: audible vocalization1
 No change
 Sound recordings
 5 7 days
 Not Reported: Communications, Developmental profile, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
DLG4 DLG4discs, large homolog 4 (Drosophila) 1742 P78352 IP/WB
Bolliger MF , et al. 2001
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
NLGN3 neuroligin 3 54413 D3DVV1 IP; LC-MS/MS
Huttlin EL , et al. 2015
SCN2A sodium channel, voltage-gated, type II, alpha 1 24766 P04775 IP/WB
Bouzidi M , et al. 2002
SNTG2 syntrophin, gamma 2 54221 Q9NY99 Y2H; IP/WB
Yamakawa H , et al. 2007

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