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Relevance to Autism

Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).

Molecular Function

The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. Mutations in this gene are associated with mental retardation autosomal dominant type 4 (MRD4; OMIM 612581).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.
DD
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Support
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
ASD
Support
Genome-wide characteristics of de novo mutations in autism.
ASD
Support
Both rare and common genetic variants contribute to autism in the Faroe Islands.
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder.
ASD
Support
Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.
ASD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.
Support
Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability.
ID
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Recent Recommendation
Examining Hippocampal Mossy Fiber Synapses by 3D Electron Microscopy in Wildtype and Kirrel3 Knockout Mice.
Recent Recommendation
The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.
Recent Recommendation
Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference.
Recent Recommendation
Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN789R001 
 translocation 
  
  
 De novo 
  
  
 GEN789R002 
 missense_variant 
 c.614G>A 
 p.Arg205Gln 
 De novo 
  
  
 GEN789R003 
 missense_variant 
 c.482G>A 
 p.Arg161His 
 De novo 
  
 Simplex 
 GEN789R004 
 translocation 
  
  
 Unknown 
  
 Unknown 
 GEN789R005 
 missense_variant 
 c.118C>T 
 p.Arg40Trp 
 Unknown 
  
 Unknown 
 GEN789R006 
 missense_variant 
 c.1007G>A 
 p.Arg336Gln 
 Unknown 
  
 Unknown 
 GEN789R007 
 missense_variant 
 c.2191G>A 
 p.Val731Phe 
 Unknown 
  
 Unknown 
 GEN789R008 
 missense_variant 
 G>C 
 p.His171Gln 
 Familial 
 Maternal 
  
 GEN789R009 
 missense_variant 
 C>T 
 p.Val30Met 
 Familial 
 Paternal 
  
 GEN789R010 
 stop_gained 
 G>A 
  
 Unknown 
  
 Unknown 
 GEN789R011 
 missense_variant 
 C>G 
 p.Lys212Asn 
 Unknown 
  
 Unknown 
 GEN789R012 
 missense_variant 
 A>G 
 p.Val303Ala 
 Unknown 
  
 Unknown 
 GEN789R013 
 missense_variant 
 c.482G>A 
 p.Arg161His 
 De novo 
  
 Simplex 
 GEN789R014 
 intron_variant 
 A>T 
  
  
  
 Unknown 
 GEN789R015 
 missense_variant 
 c.1178C>T 
 p.Ala393Val 
 Familial 
 Maternal 
  
 GEN789R016 
 missense_variant 
 c.1177G>A 
 p.Ala393Thr 
 Familial 
 Paternal 
  
 GEN789R017 
 missense_variant 
 c.1074G>T 
 p.Trp358Cys 
 Familial 
  
 Simplex 
 GEN789R018 
 missense_variant 
 c.1282C>A 
 p.Gln428Lys 
 Familial 
  
 Simplex 
 GEN789R019 
 missense_variant 
 c.1337C>T 
 p.Pro446Leu 
 Familial 
  
 Simplex 
 GEN789R020 
 missense_variant 
 c.722C>T 
 p.Ser241Leu 
 Familial 
  
 Simplex 
 GEN789R021 
 missense_variant 
 C>T 
  
 Familial 
 Maternal 
 Multiplex 
 GEN789R022 
 missense_variant 
 G>A 
  
 Familial 
 Paternal 
 Multiplex 
 GEN789R023 
 missense_variant 
 C>G 
  
 Familial 
 Maternal 
 Multiplex 
 GEN789R024 
 missense_variant 
 C>A 
  
 Familial 
 Paternal 
  
 GEN789R025 
 missense_variant 
 C>A 
  
 Familial 
 Paternal 
  
 GEN789R026 
 missense_variant 
 c.1949G>A 
 p.Arg650His 
 De novo 
  
 Multiplex 
 GEN789R027 
 missense_variant;missense_variant 
  
 p.[Arg562Leu];[Arg562Leu] 
 Familial 
 Both parents 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Duplication
 1
 
11
Duplication
 1
 
11
Deletion
 5
 
11
Duplication
 1
 
11
Deletion-Duplication
 4
 
11
Deletion-Duplication
 13
 
11
Deletion
 2
 
11
Deletion
 6
 

Model Summary

Kirrel3 null mice display preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Kirrel3 null mice show impaired ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder. Kirrel3 mice show increased locomotor activity and repetitive rearing. Kirrel3 null mice show enhanced performance on the rotarod test. Kirrel3 null mice were significantly hypersensitive to acoustic stimuli. Kirrel3 null mice show no change in anxiety-related behaviors and spatial or fear memory acquisition (Hisaoka T, et al, Sci. Rep., 2018).

References

Type
Title
Author, Year
Primary
Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.

M_KIRREL3_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Mice bearing a targeted null deletion of the entire coding region of Kirrel3 (The deleted part of the Kirrel3 gene includes the entire Kirrel3 coding region starting with the translation initiation codon in exon 1 and ending downstream of exon 16, the last exon). The targeting construct was designed to replace the Kirrel3 coding region with NLS-LacZ and the selection gene (PGK-Neo) bracketed by loxP recombination signals, which was later deleted by mating with mice expressing Cre recombinase. .
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Ozgene Pty Ltd (Bentley DC, Australia)

M_KIRREL3_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle: light phase1
Increased
Description: Mutant mice exhibit greater locomotor activity during the light phase compared with wild-type mice.
Exp Paradigm: Activity was monitored for 24 hours in the home cage.
 Home cage behavior
 Adult
General locomotor activity: Ambulatory activity1
Increased
Description: Mutants travelled greater distance compared to controls.
 Light-dark exploration test: Light-dark exploration test
 Adult
General locomotor activity1
Increased
Description: Mutants show greater motor activity in the light compartment compared to controls. Mutants show no change in motor activity in the dark compartment compared to controls. Mutants exhibit more transitions between the light and dark compartments than controls.
 Light-dark exploration test: Light-dark exploration test
 Adult
Motor coordination and balance: Motor learning1
Increased
Description: Mutants fall later from an accelarating rotarod compared to controls after the training phase.
 Accelerating rotarod test: test phase (day 2)
 Adult
General locomotor activity1
Increased
Description: Mutants show greater motor activity compared to controls.
 Elevated plus maze test
 Adult
General locomotor activity: Ambulatory activity1
Increased
Description: Mutants travelled greater distance during one-hour open field test compared to controls.
 Open field test
 Adult
Pain or nociception1
Decreased
Description: Mutants require increased current of foot show to elicit vocalization response. Mutants show no change in current level to elicit flinching or jumping responses compared to controls.
Exp Paradigm: Flinching, vocalising, and jumping behaviours were measured.
 Foot shock test
 Adult
Startle response: acoustic stimulus1
Increased
Description: Mutants show greater acoustic startle response between 85 dB and 115 dB compared to controls.
Exp Paradigm: Acoustic stimuli range: from 75 to 120 dB.
 Acoustic startle reflex test
 Adult
Social memory1
Decreased
Description: When a second social odor was introduced, control mice sniff more compared with the third presentation of the first social odour, but mutant mice do not.
 Olfactory habituation-dishabituation test
 Adult
Social dishabituation1
Decreased
Description: When a novel stimulus mouse is presented after habitutation to a familiar mouse, mutants show decreased social investigation of the novel mouse compared to controls.
 Habituation-dishabituation test
 Adult
Social memory1
Decreased
Description: Mutants spend less time sniffing a novel mouse compared to controls.
 Habituation-dishabituation test
 Adult
Rearing behavior1
Increased
Description: Mutants reared more frequently compared to controls.
 Open field test
 Adult
Social memory1
Decreased
Description: Mutants show no preference for a novel unfamiliar mouse over a familiar mouse compared to controls.
 Three-chamber social approach test
 Adult
Aggression1
Decreased
Description: Mutants show lower aggressive behavior toward a same-sex and same-strain intruder compared to wildtype controls. When mutants did attack the intruding mouse, the attack duration was shorter in mutants compared to wildtype controls.
Exp Paradigm: Same sex C57BL/6J intruder mice were used.
 Resident-intruder test
 Adult
Social dominance1
Decreased
Description: Mutants emit lower ultrasonic vocalization compared to controls.
Exp Paradigm: After an intruder mouse is introduced into a resident home cage, the resident mouse typically emits USVs to establish a social dominance.
 Resident-intruder test
 Adult
Ultrasonic vocalization: Isolation induced1
Increased
Description: Mutant pups show increased ultrasonic vocalization compared to controls when separated from their mothers.
 Monitoring ultrasonic vocalizations
 P3, P7, 2 weeks
Ultrasonic vocalization: Interaction induced: opposite sex stimulus1
Decreased
Description: Mutant male mice emit lower numbers of ultrasonic vocalizations to an oestrous female compared to wildtype controls.
Exp Paradigm: The number of ultrasonic calls during free interactions of a tested male mouse with an oestrous C57BL/6J female mouse was measured.
 Monitoring ultrasonic vocalizations
 Adult
Anxiety1
Increased
Description: Mutants prefer to walk and run on the periphery of the open field compared to controls.
 Open field test
 Adult
Targeted expression1
Decreased
Description: Mutants show no expression of 100kDa Kirrel3 protein in the olfactory bulb, cerebral cortex and hippocampus, compared to controls.
Exp Paradigm: Beta-actin was used as the loading control.
 Western blot
 Adult
Locomotor activity in diurnal cycle: dark phase1
 No change
 Home cage behavior
 Adult
Size/growth1
 No change
 Body weight measurement
 1week-4months
Anxiety1
 No change
 Elevated plus maze test
 Adult
Anxiety1
 No change
 Light-dark exploration test: Light-dark exploration test
 Adult
Exploratory activity: Habituation1
 No change
 Olfactory discrimination test
 Adult
Cognitive flexibility1
 No change
 Morris water maze test
 Adult
Cued or contextual fear conditioning: Passive avoidance1
 No change
 Passive avoidance test: short term
 Adult
Olfactory learning and memory1
 No change
 Olfactory habituation-dishabituation test
 Adult
Spatial working memory1
 No change
 Morris water maze test
 Adult
General locomotor activity: Ambulatory activity1
 No change
 Three-chamber social approach test
 Adult
Motor coordination and balance1
 No change
 Accelerating rotarod test: trial phase (day 1)
 Adult
Self grooming: home cage/familiar environment1
 No change
 Home cage behavior
 Adult; 1-2 months
Brain morphology1
 No change
 Histology: Hematoxylin and eosin staining
 Adult
Brain morphology1
 No change
 Gross necroscopy
 Adult
Brain size1
 No change
 Gross necroscopy
 Adult
Cerebellar morphology1
 No change
 Histology: Hematoxylin and eosin staining
 Adult
Hippocampal morphology1
 No change
 Histology: Hematoxylin and eosin staining
 Adult
Olfactory bulb morphology1
 No change
 Histology: Hematoxylin and eosin staining
 Adult
Repetitive digging1
 No change
 Home cage behavior
 Adult
Olfaction1
 No change
 Buried food test
 Adult
Sensorimotor gating1
 No change
 Prepulse inhibition
 Adult
Visual placing reflex1
 No change
 Visual placing test
 Adult
Social approach1
 No change
 Three-chamber social approach test
 Adult
Social habituation1
 No change
 Habituation-dishabituation test
 Adult
 Not Reported: Homeostasis, Immune response, Maternal behavior, Neurophysiology, Seizure

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