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.
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
Description: Mutants show a decrease in motor coordination and balance, evidenced by the shorter latency to fall, compared to controls.
Exp Paradigm: NA
Description: Mutants show a decrease in the post-synaptic density size, evidenced by reduced density, length, and thickness of psd, compared to controls.
Exp Paradigm: NA
Description: Mutants show a decrease in mglur-mediated ltd induced by dhpg compared to controls, with the difference evident in the last 10 min of recording.
Exp Paradigm: NA
Description: Mutants show a reduced input-output ratio in response to stepwise increase in stimulation intensity compared to controls. mutants show both reduced peak and slope compared to controls.
Exp Paradigm: NA
Description: Mutants show an increase in self-grooming compared to controls. although the duration of self-grooming is increased, there is no change in the frequency of self-grooming.
Exp Paradigm: Laboras cage
Description: Mutants show a decrease in social interaction, as evidenced by the sniffing time, chamber time, and the preference index, compared to controls.
Exp Paradigm: Chamber time, sniffing time, and preference index
Ultrasonic vocalization: interaction induced: opposite sex stimulus: simple syllables1
Decreased
Description: Mutant males show a decrease in usv short calls in response to opposite sex compared to controls. mutant males show no change in short call duration compared to controls.
Exp Paradigm: NA
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Decreased
Description: Mutant males show a decrease in the number of usvs when encounter a stranger female mouse compared to controls. the time to emission of the first usv call was not changed.
Exp Paradigm: NA
Description: Mutants show a decrease in the number of usvs compared to controls. mutants also take longer to emit the first usv calls on p9 but not on p7 or p11 compared to controls. moreover, mutants show a decrease in usv harmonic calls in response to isolation compared to controls as well as a decrease in harmonic call duration compared to controls. however, mutants show no change in usv short calls and their duration in response to isolation compared to controls.
Exp Paradigm: NA
Description: Mutants show an increase in anxiety, evidenced by decreased number of entries into light chamber, decreased time spent in the light chamber, and percent of time spent in the light chamber, compared to controls.
Exp Paradigm: NA
Description: Mutants show a decrease in cognitive flexibility, evidenced by decreased number of platform crossings during reversal trial, compared to controls. this was not due to change in swimming ability.
Exp Paradigm: NA
Description: Mutants show a decrease in spatial reference memory, evidenced by increased latency to escape as well as decreased target quadrant occupancy in probe trial, compared to controls.
Exp Paradigm: Probe trial
