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Relevance to Autism

Studies have found rare mutations in the IL1RAPL1 gene that are associated with autism (e.g. Bhat et al., 2008) as well as with developmental delay and intellectual disability (Mikhail et al., 2011).

Molecular Function

This protein may regulate calcium-dependent exocytosis.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism.
ASD
Support
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
DD, hypotonia, dysmorphic features
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.
ID
Support
Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.
ASD
Support
Whole exome sequencing in females with autism implicates novel and candidate genes.
ASD
Support
Functional impact of global rare copy number variation in autism spectrum disorders.
ASD
Support
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
ID
Support
Mutations in the calcium-related gene IL1RAPL1 are associated with autism.
ASD
MR
Support
Etiological yield of SNP microarrays in idiopathic intellectual disability.
DD, ID
ASD or autistic features, epilepsy
Support
Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes.
DD, ID
Support
Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.
ASD, DD
Support
Genetic Diagnostic Evaluation of Trio-Based Whole Exome Sequencing Among Children With Diagnosed or Suspected Autism Spectrum Disorder.
ASD
DD/ID, epilepsy/seizures
Support
Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.
ID
ASD
Highly Cited
IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exoc...
Recent Recommendation
A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation.
Recent Recommendation
A study on the correlation between IL1RAPL1 and human cognitive ability.
Recent Recommendation
Genome-wide detection of tandem DNA repeats that are expanded in autism
ASD
Recent Recommendation
IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+channel and neurite elongation.
Recent Recommendation
The X-linked intellectual disability protein IL1RAPL1 regulates dendrite complexity.
Recent Recommendation
Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.
ID
DD
Recent Recommendation
IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons thro...
Recent Recommendation
Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...
DD
ID

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN133R001 
 frameshift_variant 
 c.1730del 
 p.Glu577GlyfsTer24 
 De novo 
 NA 
 Simplex 
 GEN133R002 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN133R003 
 missense_variant 
 c.1136A>G 
 p.Lys379Arg 
 Familial 
 Maternal 
  
 GEN133R004 
 missense_variant 
 c.1854A>T 
 p.Gln618His 
 Familial 
 Maternal 
  
 GEN133R005 
 inversion 
  
  
 Familial 
 Maternal 
  
 GEN133R006 
 copy_number_loss 
  
  
 Familial 
 Maternal 
  
 GEN133R007 
 copy_number_gain 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN133R008 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN133R009 
 frameshift_variant 
 c.779-65850del 
  
 De novo 
 NA 
  
 GEN133R010 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN133R011 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN133R012 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN133R013 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN133R014 
 copy_number_gain 
  
  
 De novo 
 NA 
  
 GEN133R015 
 copy_number_loss 
 c.1213_1287del 
 p.Tyr405_Phe429del 
 Familial 
 Maternal and paternal 
 Multi-generational 
 GEN133R016 
 copy_number_loss 
 c.703+99897_778+59920del 
 p.Ala235_Leu259del 
 Familial 
 Maternal 
 Multiplex 
 GEN133R017 
 missense_variant 
 c.91T>C 
 p.Cys31Arg 
 Familial 
 Maternal 
 Multiplex 
 GEN133R018 
 missense_variant 
 c.1433C>A 
 p.Thr478Asn 
 Unknown 
  
 Multiplex 
 GEN133R019 
 frameshift_variant 
 c.894_903del 
 p.Trp299ThrfsTer18 
 Familial 
 Maternal 
 Multiplex 
 GEN133R020 
 translocation 
  
  
 De novo 
 NA 
  
 GEN133R021 
 translocation 
  
  
 De novo 
 NA 
  
 GEN133R022 
 stop_gained 
 c.1489C>T 
 p.Arg497Ter 
 De novo 
 NA 
 Simplex 
 GEN133R023 
 translocation 
  
  
 De novo 
 NA 
  
 GEN133R024 
 minisatellite 
  
  
 Unknown 
  
 Unknown 
 GEN133R025 
 minisatellite 
  
  
 Unknown 
  
 Unknown 
 GEN133R026 
 minisatellite 
  
  
 Unknown 
  
 Unknown 
 GEN133R027 
 minisatellite 
  
  
 Unknown 
  
 Unknown 
 GEN133R028 
 minisatellite 
  
  
 Unknown 
  
 Unknown 
 GEN133R029 
 minisatellite 
  
  
 Unknown 
  
 Unknown 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 17
 
X
Deletion-Duplication
 12
 
X
Deletion
 1
 
X
Duplication
 6
 
X
Deletion
 1
 
X
Deletion
 1
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 

Model Summary

KO mouse show a reduction of both dendritic spine density and excitatory synapses in the CA1 region of the hippocampus associated with specific deficits in hippocampal long-term synaptic plasticity.

References

Type
Title
Author, Year
Primary
A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation.
Additional
IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours.

M_IL1RAPL1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene targeted deletion of fifth exon of the Il1rapl1 gene resulting in a disruption of the ORF after transcription and splicing of exon 4-6 which leads to a premature STOP codon of the extracellular domain.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6N
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Charles River

M_IL1RAPL1_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: The targeting vector was constructed by replacing exon 3 with a pgk-neo cassette. The linearized vector, containing the long and short arms for initiating recombination derived from a BAC, was used for electroporation and generation of chimeric mice. This resulted in the loss of IL1RAPL1 protein in the brain.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6
ES Cell Line: RENKA
Mutant ES Cell Line:
Model Source:

M_IL1RAPL1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synapse density1
Decreased
Description: Decreased number of asymmetric axospinous contacts in the stratum radiatum of the ca1 area of the hippocampus
Exp Paradigm: Stereology and electron microscopy of the ca1 area of the hippocampus- electron microscopy
 Electron microscopy
 Unreported
Dendritic architecture: spine density1
Decreased
Description: Decreased density of spines on apical and basal dendrites of ca1 pyramidal neurons
Exp Paradigm: Diolistic fluorescent labeling
 Histology
 Unreported
Dendritic architecture: spine density1
Decreased
Description: Decreased density of postsynaptic spines on secondary and tertiary dendritic segments of ca1 pyramidal neurons
Exp Paradigm: Diolistic fluorescent labeling
 Histology
 Unreported
Synapse density1
Decreased
Description: Decreased number of asymmetric axospinous contacts in the stratum radiatum of the ca1 area of the hippocampus
Exp Paradigm: Stereology and electron microscopy of the ca1 area of the hippocampus-stereology
 Stereology
 Unreported
Synaptic plasticity1
Decreased
Description: Decreased long term potentiation stimulated at hippocampal sc-ca1 synapse by tbs
Exp Paradigm: Ltp measured by patch clamp in hippocampal sc-ca1 synapse after theta-burst stimulation (tbs)
 Whole-cell patch clamp
 Unreported
Brain cytoarchitecture1
 No change
 Electron microscopy
 Unreported
Brain cytoarchitecture1
 No change
 Electron microscopy
 Unreported
Brain cytoarchitecture1
 No change
 Electron microscopy
 Unreported
Brain morphology1
 No change
 Electron microscopy
 Unreported
Brain morphology1
 No change
 Confocal microscopy
 Unreported
Presynaptic function: paired-pulse facilitation1
 No change
 Paired-pulse ratio
 Unreported
Synaptic plasticity1
 No change
 Whole-cell patch clamp
 Unreported
Synaptic transmission1
 No change
 Field potential recordings
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_IL1RAPL1_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Grip strength1
Decreased
Description: Il1rap1 null mice have a shorter latency of falling off in the wire hang test compared to wt, therefore show some decrease in grip strength
Exp Paradigm: NA
 Wire hang test
 11-14 weeks
General locomotor activity: ambulatory activity1
Increased
Description: Il1rap1 null mice show increased locomotor activity compared to wt mice in distance traveled in open field test and elevated-plus maze
Exp Paradigm: Open field test
 Open field test
 11-14 weeks
General locomotor activity: ambulatory activity1
Increased
Description: Il1rap1 null mice show increased locomotor activity compared to wt mice in distance traveled in open field test and elevated-plus maze
Exp Paradigm: Elevated plus maze test
 Elevated plus maze test
 11-14 weeks
Motor coordination and balance1
Increased
Description: Il1rap1 null mice show improved performance than wt mice in the accelerating rotarod test, having a longer latency to fall
Exp Paradigm: NA
 Accelerating rotarod test
 11-14 weeks
Dendritic architecture: spine density1
Decreased
Description: The spine density is significantly reduced in the hippocampal and layer2/3 pyramidal neurons in il1rap1 null mice, compared to wt mice
Exp Paradigm: NA
 Confocal microscopy
 3 weeks
Social approach1
Increased
Description: Il1rap1 null mice surprisingly show improved sociability in the three-chambered social approach test spending more time sniffing the cage containing the stranger mouse than the empty cage
Exp Paradigm: NA
 Three-chamber social approach test
 11-14 weeks
Anxiety1
Decreased
Description: Il1rap1 null mice show reduced anxiety by spending more time in the center of the open field and in the open arms of the elevated-plus maze
Exp Paradigm: Open field test: time spent in the center
 Open field test
 11-14 weeks
Anxiety1
Decreased
Description: Il1rap1 null mice show reduced anxiety by spending more time in the center of the open field and in the open arms of the elevated-plus maze
Exp Paradigm: Elevated plus maze test
 Elevated plus maze test
 11-14 weeks
Cued or contextual fear conditioning: memory of cue: long term recall1
Decreased
Description: Il1rap1 null mice continue to have poor retention of the conditioning cue 28 days after fear conditioning compared to wt mice
Exp Paradigm: NA
 Fear conditioning test
 11-14 weeks
Cognitive flexibility1
Decreased
Description: Il1rap1 null mice have reduced acquisition of reversal learning, where the position of the reward food pellet in changed, in both the barnes maze and t-maze tests
Exp Paradigm: Barnes maze test: reversal learning and probe test
 Barnes maze test
 11-14 weeks
Spatial reference memory1
Decreased
Description: Il1rap1 null mice show poorer memory in retention of the barnes baze task on the second probe test conducted 29 days after the training. there is no differnence between genotypes in retention when the probe test is conducted one day after training.
Exp Paradigm: NA
 Barnes maze test
 11-14 weeks
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Il1rap1 null mice have poor retention of conditioning cue one day after training in fear conditioning test
Exp Paradigm: NA
 Fear conditioning test
 11-14 weeks
Reward reinforced choice behavior1
Decreased
Description: Il1rap1 null mice show poor acquisition of spatial memory reinforced by food pellets as reward, in both t maze test and banes maze test.
Exp Paradigm: T-maze test: forced alternation (food reward)
 T-maze test
 11-14 weeks
Cued or contextual fear conditioning1
Decreased
Description: Il1rap1 null mice show reduced freezing in the fear conditioning test
Exp Paradigm: NA
 Fear conditioning test
 11-14 weeks
Reward reinforced choice behavior1
Decreased
Description: Il1rap1 null mice show poor acquisition of spatial memory reinforced by food pellets as reward, in both t maze test and banes maze test.
Exp Paradigm: Barnes maze test: food reward
 Barnes maze test
 11-14 weeks
Cognitive flexibility1
Decreased
Description: Il1rap1 null mice have reduced acquisition of reversal learning, where the position of the reward food pellet in changed, in both the barnes maze and t-maze tests
Exp Paradigm: T-maze test: reversal learning
 T-maze test
 11-14 weeks
Spatial working memory1
Decreased
Description: Il1rap1 null mice show reduced working/reference memory in the barnes maze test as they make more errors and have longer escape latencies compared to wt mice.
Exp Paradigm: NA
 Barnes maze test
 11-14 weeks
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 11-14 weeks
Developmental trajectory1
 No change
 General observations
 11-14 weeks
Size/growth1
 No change
 Body weight measurement
 11-14 weeks
Anxiety1
 No change
 Light-dark exploration test
 11-14 weeks
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 11-14 weeks
Cued or contextual fear conditioning: memory of context: long term recall1
 No change
 Fear conditioning test
 11-14 weeks
Grip strength1
 No change
 Grip strength test
 11-14 weeks
Brain size1
 No change
 NA
 3 weeks
Pain or nociception1
 No change
 Hot plate test
 11-14 weeks
Sensorimotor gating1
 No change
 Prepulse inhibition
 11-14 weeks
Startle response: acoustic stimulus1
 No change
 Acoustic startle reflex test
 11-14 weeks
Social memory1
 No change
 Three-chamber social approach test
 11-14 weeks
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, 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 Y2H; GST; IP/WB
Pavlowsky A , et al. 2010
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
MAPK8 mitogen-activated protein kinase 8 5599 P45983 Luciferase reporter assay
Khan JA , et al. 2004
NCS-1 neuronal calcium sensor 1 23413 P62166 Y2H; GST; IP/WB
Bahi N , et al. 2003
PTPRD protein tyrosine phosphatase, receptor type, D 5789 P23468 IP/WB; Cell aggregation assay
Ramos-Brossier M , et al. 2014
DLG4 Postsynaptic density protein 95 13385 Q62108 IP; LC-MS/MS
Frank RA , et al. 2016
Ptprd protein tyrosine phosphatase, receptor type, D 19266 Q64487 Co-crystal structure; Surface plasmon resonance (SPR)
Yamagata A , et al. 2015

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