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Relevance to Autism

Lrfn2 knockout mice were shown to exhibit autism-like behavioral abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits in Morimura et al., 2017; functionally deficient LRFN2 missense variants were identified in Japanese autism and schizophrenia patients in the same report.

Molecular Function

The protein encoded by the LRFN2 gene promotes neurite outgrowth in hippocampal neurons, enhances the cell surface expression of 2 NMDA receptor subunits GRIN1 and GRIN2A, and may play a role in redistributing DLG4 to the cell periphery.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.
ASD, SCZ
Positive Association
Genome-wide association study of antisocial personality disorder.
Antisocial personality disorder
Support
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Heterozygous deletion of the LRFN2 gene is associated with working memory deficits.
Learning disability
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN911R001 
 missense_variant 
 c.210G>C 
 p.Gln70His 
 Unknown 
  
  
 GEN911R002 
 missense_variant 
 c.565G>A 
 p.Ala189Thr 
 Unknown 
  
  
 GEN911R003 
 missense_variant 
 c.698C>T 
 p.Pro233Leu 
 Unknown 
  
  
 GEN911R004 
 missense_variant 
 c.740A>T 
 p.Asn247Ile 
  
  
  
 GEN911R005 
 missense_variant 
 c.797G>T 
 p.Gly266Val 
 Unknown 
  
  
 GEN911R006 
 missense_variant 
 c.821G>A 
 p.Arg274His 
 Familial 
 Paternal 
 Simplex 
 GEN911R007 
 missense_variant 
 c.1009G>A 
 p.Ala337Thr 
 Unknown 
  
  
 GEN911R008 
 missense_variant 
 c.1286C>A 
 p.Ser429Tyr 
  
  
  
 GEN911R009 
 missense_variant 
 c.1386G>C 
 p.Glu462Asp 
 Familial 
  
 Simplex 
 GEN911R010 
 missense_variant 
 c.1462G>A 
 p.Asp488Asn 
  
  
  
 GEN911R011 
 missense_variant 
 c.1418A>T 
 p.Asn473Ile 
 Unknown 
  
  
 GEN911R012 
 missense_variant 
 c.2308G>A 
 p.Asp770Asn 
 Unknown 
  
  
 GEN911R013 
 frameshift_variant 
 c.643del 
 p.Asp215IlefsTer12 
 De novo 
  
 Simplex 
 GEN911R014 
 missense_variant 
 c.1160G>A 
 p.Ser387Asn 
 De novo 
  
 Simplex 
 GEN911R015 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN911R016 
 missense_variant 
 c.1229G>A 
 p.Gly410Glu 
 De novo 
  
 Simplex 
 GEN911R017 
 missense_variant 
 c.983G>A 
 p.Arg328His 
 De novo 
  
 Simplex 
 GEN911R018 
 missense_variant 
 c.1850G>A 
 p.Arg617His 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
6
Deletion-Duplication
 12
 
6
Deletion-Duplication
 10
 
6
Deletion
 2
 
6
Deletion
 1
 

Model Summary

Lrfn2 homozygous null mice exhibit decreased body weight, social interaction, social approach, mating-induced USV, expression of the presynaptic protein PSD-95, spine density in the pyramidal neurons of the hippocampal CA1 region, length of the postsynaptic density, mEPSC frequency, GluA1 in the postsynaptic density and increase social withdrawal, number of silent synapses compared to wildtype controls.

References

Type
Title
Author, Year
Primary
Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Mice with exon 2 of Lrfn2 replaced by a neo cassette. The neo cassette was removed by germline Cre recombination and heterozygous knockouts were backcrossed to C57BL/6J for six generations.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line:
Mutant ES Cell Line: E14
Model Source: 28604739
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hyperactivity1
Increased
 Running wheel test
 2-6 months
Neuroreceptor levels: glutamate receptors: nmda receptors1
Increased
 Western blot
 8 week
Synaptic morphology: active zone1
Decreased
 Immunohistochemistry
 8 week
Neuroreceptor levels: glutamate receptors: nmda receptors1
Increased
 Quantitative pcr (qrt-pcr)
 8 week
Synaptic morphology: synaptic cleft length1
Increased
 Electron microscopy
 8 week
Synaptic morphology1
Abnormal
 Electron microscopy
 8 week
Dendritic architecture: spine morphology1
Abnormal
 Golgi-cox staining
 8 week
Synaptic morphology: active zone1
Decreased
 Western blot
 8 week
Post-synaptic density size1
Decreased
 Electron microscopy
 8 week
Dendritic architecture: spine density1
Decreased
 Golgi-cox staining
 8 week
Synaptic morphology: active zone1
Decreased
 Quantitative pcr (qrt-pcr)
 8 week
Decay kinetics of evoked post synaptic currents1
Decreased
 Whole-cell patch clamp
 8-14 weeks
Synaptic plasticity: hippocampal ltp1
Increased
 Long term potentiation (ltp)
 8-14 weeks
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Increased
 Whole-cell patch clamp
 8-14 weeks
Miniature post synaptic current frequency: excitatory1
Decreased
 Whole-cell patch clamp
 8-14 weeks
Synaptic transmission1
Decreased
 Whole-cell patch clamp
 8-14 weeks
Perseveration1
Increased
 Running wheel test
 2-6 months
Perseveration1
Increased
 Marble-burying test
 2-6 months
Sensorimotor gating1
Increased
 Prepulse inhibition
 2-6 months
Startle response: acoustic stimulus1
Increased
 Acoustic startle reflex test
 2-6 months
Social withdrawal1
Increased
 Reciprocal social interaction test
 2-6 months
Social interaction1
Decreased
 Reciprocal social interaction test
 2-6 months
Social approach1
Decreased
 Three-chamber social approach test
 2-6 months
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Decreased
 Monitoring ultrasonic vocalizations
 2-6 months
Size/growth1
Decreased
 Body weight measurement
 6-10 weeks
Spatial reference memory1
Increased
 Morris water maze test
 2-6 months
Cued or contextual fear conditioning: memory of context: long term recall1
Increased
 Fear conditioning test
 2-6 months
Cued or contextual fear conditioning: memory of context1
Increased
 Fear conditioning test
 2-6 months
Targeted expression1
Decreased
 Western blot
 Adult
Protein localization: synapse1
Decreased
 Western blot
 NA
Ultrasonic vocalization: isolation induced1
 No change
 Monitoring ultrasonic vocalizations
 0-3weeks
Mortality/lethality1
 No change
 Genotypic ratio of progeny from heterozygous parents
 3-8 weeks
Anxiety1
 No change
 Elevated plus maze test
 2-6 months
Anxiety1
 No change
 Light-dark exploration test
 2-6 months
Anxiety1
 No change
 Open field test
 2-6 months
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 2-6 months
Spatial working memory1
 No change
 Morris water maze test
 2-6 months
Protein localization: synapse1
 No change
 Western blot
 NA
General locomotor activity1
 No change
 Home cage behavior
 2-6 months
General locomotor activity: ambulatory activity1
 No change
 Home cage behavior
 2-6 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 2-6 months
Brain anatomy1
 No change
 Histology
 Adult
Neuronal number: excitatory neurons1
 No change
 Immunohistochemistry
 5-8 month
Neuronal number: inhibitory neurons1
 No change
 Immunohistochemistry
 5-8 month
Neuroreceptor levels: glutamate receptors: ampa receptors1
 No change
 Western blot
 8 week
Neuroreceptor levels: glutamate receptors: nmda receptors1
 No change
 Quantitative pcr (qrt-pcr)
 8 week
Neuroreceptor levels: glutamate receptors: nmda receptors1
 No change
 Western blot
 8 week
Synaptic morphology: active zone1
 No change
 Western blot
 8 week
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 8-14 weeks
Neurotransmitter release1
 No change
 Paired-pulse ratio
 8-14 weeks
Reproductive function1
 No change
 General observations
 Adult
Repetitive digging1
 No change
 Reciprocal social interaction test
 2-6 months
Olfaction1
 No change
 Response to olfactory stimuli
 2-6 months
Pain or nociception1
 No change
 Foot shock test
 2-6 months
Vision1
 No change
 Morris water maze test
 2-6 months
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Physiological parameters, Seizure

 

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