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Relevance to Autism

Rare de novo variants in the LRRC4 gene (one damaging missense, one loss-of-function) have been identified in ASD probands (Jiang et al., 2013; De Rubeis et al., 2014). Lrrc4 -/- mice were found to display mildly reduced social interaction, suppressed social communication, repetitive behaviors, impaired spatial learning, mild anxiety-like behaviors, suppressed excitatory synapse density and function in the hippocampus, and suppressed excitatory transmission and NMDAR- and mGluR-dependent synaptic plasticity (Um et al., 2018).

Molecular Function

The LRRC4 gene encodes a synaptic adhesion protein that regulates the formation of exitatory synapses through the recruitment of pre-and-postsynaptic proteins and organizes the lamina/pathway-specific differentiation of dendrites.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.
ASD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Recent Recommendation
NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1020R001 
 missense_variant 
 c.238C>G 
 p.Leu80Val 
 De novo 
  
 Simplex 
 GEN1020R002 
 frameshift_variant 
 c.10_11del 
 p.Leu4ValfsTer50 
 De novo 
  
  
 GEN1020R003 
 missense_variant 
 c.122C>T 
 p.Ala41Val 
 Unknown 
  
  
 GEN1020R004 
 missense_variant 
 c.695A>C 
 p.Glu232Ala 
 De novo 
  
  
 GEN1020R005 
 missense_variant 
 c.238C>G 
 p.Leu80Val 
 De novo 
  
  
 GEN1020R006 
 synonymous_variant 
 c.1188C>T 
 p.Ser396%3D 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
7
Deletion
 2
 
7
Deletion
 1
 
7
Deletion
 1
 
7
Duplication
 4
 
7
Deletion
 2
 
7
Deletion-Duplication
 10
 

Model Summary

Lrrc4 deletion results in a number of behavioral deficits, including decreased social interaction, suppressed social communication, increased grooming, impaired spatial learning, and increased anxiety. Lrrc4 deletion results in reduced NMDAR- and AMPAR- mediated synaptic transmission, NMDAR-dependent synaptic plasticity (LTP), and mGluR-dependent LTD. Treatment with NMDAR receptor agonist DCS rescues social interaction deficits and increased self-grooming asd well as hippocampal LTP and LTD, but has no effect on USVs deficits or increased anxiety.

References

Type
Title
Author, Year
Primary
NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Knockout mice were generated lacking exon 1 of the mouse Lrrc4 gene, which contains the complete coding region of the gene and is the only exon in the gene.
Allele Type: Knockout
Strain of Origin: C57BL/6-Tyrc-Brd * 129S5/SvEvBrd
Genetic Background: C57BL/6N
ES Cell Line: 129S5/SvEvBrd
Mutant ES Cell Line:
Model Source: Mutant Mouse Resource and Reasearch Center
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming: home cage/familiar environment1
Increased
 Home cage behavior
 3-5 months
Motor coordination and balance1
Decreased
 Accelerating rotarod test
 3-5 months
Climbing1
Decreased
 Automated animal behavior recognition cage
 3 months
Post-synaptic density size1
Decreased
 Electron microscopy
 P21
Dendritic architecture: spine density1
Decreased
 Immunohistochemistry
 P20-23
Dendritic architecture: spine density1
Decreased
 Golgi-cox staining
 2-3 months
Epsp-spike relationship1
Decreased
 Field potential recordings
 P21-25
Synaptic plasticity: hippocampal ltp1
Decreased
 Field potential recordings
 2-3 months
Miniature post synaptic current frequency: excitatory1
Decreased
 Whole-cell patch clamp
 P21-25
Synaptic plasticity: hippocampal ltd: nmdar-mediated1
Decreased
 Field potential recordings
 P17p22
Miniature post synaptic current amplitude: excitatory1
Decreased
 Whole-cell patch clamp
 P21-23
Synaptic plasticity: hippocampal ltd: mglur-mediated1
Decreased
 Field potential recordings
 P21p25
Miniature post synaptic current amplitude: excitatory1
Decreased
 Whole-cell patch clamp
 P21-25
Synaptic plasticity: hippocampal ltp1
Decreased
 Field potential recordings
 P25-30
Miniature post synaptic current frequency: excitatory1
Decreased
 Whole-cell patch clamp
 P21-23
Self grooming: perseveration1
Increased
 Automated animal behavior recognition cage
 3-5 months
Social approach1
Decreased
 Three-chamber social approach test
 3-5 months
Ultrasonic vocalization: isolation induced1
Decreased
 Monitoring ultrasonic vocalizations
 P7-11
Ultrasonic vocalization: interaction induced: opposite sex stimulus: simple syllables1
Decreased
 Monitoring ultrasonic vocalizations
 2 months
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Decreased
 Monitoring ultrasonic vocalizations
 2 months
Anxiety1
Increased
 Light-dark exploration test
 3 months
Spatial reference memory1
Decreased
 Morris water maze test
 5 months
Spatial learning1
Decreased
 Morris water maze test
 5 months
Cognitive flexibility1
Decreased
 Morris water maze test
 5 months
Targeted expression1
Decreased
 Western blot
 P21-22
Adaptation to dark phase1
 No change
 Automated animal behavior recognition cage
 3 months
Locomotor activity in diurnal cycle: light phase1
 No change
 Automated animal behavior recognition cage
 3 months
Ultrasonic vocalization: interaction induced: opposite sex stimulus: complex syllables1
 No change
 Monitoring ultrasonic vocalizations
 2 months
Anxiety1
 No change
 Elevated plus maze test
 3-5 months
Anxiety1
 No change
 Open field test
 3-5 months
Object recognition memory1
 No change
 Novel object recognition test
 3 months
Spatial reference memory1
 No change
 Morris water maze test
 5 months
Pup retrieval1
 No change
 Pup retrieval assay
 3 months
Protein expression level evidence1
 No change
 Western blot
 P21-22
Protein expression level evidence1
 No change
 Fluorescence microscopy
 Not reported
General locomotor activity: ambulatory activity1
 No change
 Open field test
 3-5 months
Swimming ability1
 No change
 Morris water maze test
 5 months
Dendritic architecture: dendritic tree complexity1
 No change
 Sholl analysis
 P21-24
Hippocampal morphology1
 No change
 Immunohistochemistry
 P28
Post-synaptic density size: excitatory synapses1
 No change
 Electron microscopy
 P21
Decay kinetics of evoked post synaptic currents1
 No change
 Field potential recordings
 P21-25
Miniature post synaptic current amplitude: inhibitory1
 No change
 Whole-cell patch clamp
 P21-23
Miniature post synaptic current frequency: excitatory1
 No change
 Whole-cell patch clamp
 P21-25
Miniature post synaptic current frequency: inhibitory1
 No change
 Whole-cell patch clamp
 P21-23
Presynaptic function: paired-pulse facilitation1
 No change
 Field potential recordings
 P21-25
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
 No change
 Field potential recordings
 P21-25
Rearing behavior1
 No change
 Automated animal behavior recognition cage
 3 months
Social memory1
 No change
 Three-chamber social approach test
 3-5 months
 Not Reported: Developmental profile, Immune response, Physiological parameters, Seizure, Sensory

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