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Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) but not T-type (CACNA1G).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo gene disruptions in children on the autistic spectrum.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
ASD
Support
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
Dysmorphic features
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN656R001 
 splice_site_variant 
 c.2057-2A>G 
  
 De novo 
 NA 
 Simplex 
 GEN656R002 
 stop_gained 
 c.1522G>T 
 p.Glu508Ter 
 De novo 
 NA 
 Simplex 
 GEN656R003 
 missense_variant 
 c.1733G>A 
 p.Arg578Gln 
 Familial 
  
 Simplex 
 GEN656R004 
 missense_variant 
 c.2092G>A 
 p.Ala698Thr 
 Familial 
  
 Simplex 
 GEN656R005 
 missense_variant 
 c.2266G>A 
 p.Asp756Asn 
 Familial 
  
 Simplex 
 GEN656R006 
 missense_variant 
 c.2191C>G 
 p.Arg731Gly 
 Familial 
  
 Simplex 
 GEN656R007 
 missense_variant 
 c.1993C>T 
 p.Arg665Cys 
 Unknown 
  
 Unknown 
 GEN656R008 
 missense_variant 
 c.613C>G 
 p.Arg205Gly 
 Unknown 
  
 Unknown 
 GEN656R009 
 missense_variant 
 c.2318C>T 
 p.Ala773Val 
 Familial 
 Maternal 
  
 GEN656R010 
 missense_variant 
 c.2318C>T 
 p.Ala773Val 
 Familial 
 Maternal 
  
 GEN656R011 
 missense_variant 
 c.823G>A 
 p.Ala275Thr 
 Familial 
 Paternal 
  
 GEN656R012 
 translocation 
  
  
 De novo 
 NA 
  
 GEN656R013 
 splice_site_variant 
 A>T 
 p.? 
 Familial 
  
 Multiplex 
 GEN656R014 
 splice_site_variant 
 c.1398+1G>A 
  
 Familial 
 Maternal 
 Simplex 
 GEN656R015 
 missense_variant 
 c.2749G>A 
 p.Ala917Thr 
 Familial 
 Maternal 
 Simplex 
 GEN656R016 
 missense_variant 
 c.2093C>T 
 p.Ala698Val 
 Familial 
 Maternal 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion-Duplication
 15
 
3
Deletion
 7
 
3
Deletion
 1
 
3
Deletion
 2
 
3
Deletion
 1
 

Model Summary

CACNA2D3 homozygous knockout mice show lessened or a complete loss of sensitivity to thermal pain, impaired transmission of heat-induced pain signals from the thalamus to the somatosensory cortex, and impaired signaling in the somatosensory cingulate and motor cortices after exposure to noxious temperatures. Paradoxically, heat and touch trigger strong cross activation in brain regions involved in sight, smell and hearing in the CACNA2D3 mutant mice.

References

Type
Title
Author, Year
Primary
A genome-wide Drosophila screen for heat nociception identifies 23 as an evolutionarily conserved pain gene.

M_CACNA2D3_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: CACNA2D3 mutant mice were generated by homologous recombination. A targeting vector containing a lacz reporter was inserted into exon 15 of the murine CACNA2D3 gene. Germline-transmitted F1 mice were backcrossed onto a C57BL/6 background.
Allele Type: Targeted(knockout)
Strain of Origin: 129/OlaHsd mouse substrain
Genetic Background: C57BL/6
ES Cell Line: 129/OlaHsd mouse substrain
Mutant ES Cell Line:
Model Source: Unreported

M_CACNA2D3_1_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: CACNA2D3 mutant mice were generated by homologous recombination. A targeting vector containing a lacz reporter was inserted into exon 15 of the murine CACNA2D3 gene. Germline-transmitted F1 mice were backcrossed onto a C57BL/6 background.
Allele Type: Targeted(knockout)
Strain of Origin: 129/OlaHsd mouse substrain
Genetic Background: C57BL/6
ES Cell Line: 129/OlaHsd mouse substrain
Mutant ES Cell Line:
Model Source: Unreported

M_CACNA2D3_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal activation following behavioral stimulation1
Increased
Description: CACNA2D3 homozygous knockout mice showed increased cross-neuronal activation in brain regions involved in sight, hearing and smell following thermal or tactile stimulation, compared to control mice
Exp Paradigm: Noninvasive functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) signal, males only, calculated cross-correlation matrix of the response time profiles for each predefined region of the somatosensory pain matrix
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Network excitability1
Decreased
Description: CACNA2D3 homozygous knockout mice showed impaired signaling in the somatosensory S1 and S2 cortices, cingulate, or motor cortex after exposure to noxious temperatures. CACNA2D3 homozygous knockout mice showed reduction in transmission of pain signal from the left to the right brain and increased intracortical inhibition compared to controls. CACNA2D3 homozygous knockout mice showed no change in total functional connectivity within the pain matrix and multisensory-thalamo-cortical network connectivity compared to controls.
Exp Paradigm: Noninvasive functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) signal, males only, calculated cross-correlation matrix of the response time profiles for each predefined region of the somatosensory pain matrix
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Functional magnetic resonance imaging: connectivity1
Decreased
Description: CACNA2D3 homozygous knockout mice showed intact signaling in the thalamus but impaired signaling in the somatosensory S1 and S2 cortices, cingulate, or motor cortex after exposure to noxious temperatures whereas in controls thermal stimuli activate the entire brain-pain-matrix including the thalamus, the S1 and S2 somatosensory cortex, the cingulum, amygdala, hypothalamus, or the motor cortex after exposure to noxious temperatures, CACNA2D3 homozygous knockout mice showed reduction in transmission of pain signal from the left to the right brain and increased intracortical inhibition compared to controls, CACNA2D3 homozygous knockout mice showed no change in total functional connectivity within the pain matrix and multisensory-thalamo-cortical network connec
Exp Paradigm: Noninvasive functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) signal, males only, calculated cross-correlation matrix of the response time profiles for each predefined region of the somatosensory pain matrix
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Functional magnetic resonance imaging1
Increased
Description: CACNA2D3 homozygous knockout mice showed increased total brain BOLD fMRI activation for tactile vibrissal stimulation, compared to controls
Exp Paradigm: Noninvasive functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) signal, males only, calculated cross-correlation matrix of the response time profiles for each predefined region of the somatosensory pain matrix
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Pain or nociception: thermal1
Decreased
Description: CACNA2D3 homozygous knockout mice showed impaired thermal nociception mediated by pain centers in the brain compared to controls. CACNA2D3 homozygous knockout mice showed delayed thermal sensitization of peripheral inflammatory pain compared to controls although general inflammation determined by paw swelling was normal in CACNA2D3 heterozygous knockout mice compared to controls, indicating CACNA2D3 contributes to the acute phase of heat hyperalgesia
Exp Paradigm: Thermal responsiveness measured at 50, 52, 54, and 56degrees centigrade. Males and females tested. Complete Freunds Adjuvant (CFA) model of peripheral inflammatory pain.-Hot plate test: brain mediated thermal pain response
 Hot plate test
 Adult
Pain or nociception: thermal1
Decreased
Description: CACNA2D3 homozygous knockout mice showed impaired thermal nociception mediated by pain centers in the brain compared to controls. CACNA2D3 homozygous knockout mice showed delayed thermal sensitization of peripheral inflammatory pain compared to controls although general inflammation determined by paw swelling was normal in CACNA2D3 heterozygous knockout mice compared to controls, indicating CACNA2D3 contributes to the acute phase of heat hyperalgesia
Exp Paradigm: Thermal responsiveness measured at 50, 52, 54, and 56degrees centigrade. Males and females tested. Complete Freunds Adjuvant (CFA) model of peripheral inflammatory pain.- Local inflammatory reaction
 Local inflammatory reaction
 Adult
Targeted expression1
Decreased
Description: CACNA2D3 homozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, and the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only-Southern blot
 Southern blot
 Adult
Targeted expression1
Decreased
Description: CACNA2D3 homozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, and the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only- Western blot
 Western blot
 Adult
Targeted expression1
Decreased
Description: CACNA2D3 homozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, and the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only- Immunohistochemistry
 Immunohistochemistry
 Adult
General characteristics1
 No change
 General observations
 Adult
Size/growth1
 No change
 Body weight measurement
 1.6, 3, 6, and 10 months
Anxiety1
 No change
 Open field test
 Adult
Depression1
 No change
 Tail suspension test
 Adult
Exploratory activity1
 No change
 Open field test
 Adult
Inflammatory response1
 No change
 Local inflammatory reaction
 Adult
Inflammatory response1
 No change
 General observations
 Adult
General locomotor activity1
 No change
 Open field test
 Adult
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Adult
Functional magnetic resonance imaging1
 No change
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Functional magnetic resonance imaging1
 No change
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Ion influx and permeability: calcium1
 No change
 Whole-cell patch clamp
 Adult
Neuronal activation1
 No change
 Functional magnetic resonance imaging (fmri)-resting state
 Adult
Glucose levels1
 No change
 Measurement of blood glucose
 Adult
Homeostasis1
 No change
 General observations
 Adult
Homeostasis1
 No change
 General observations
 Adult
Renal function1
 No change
 General observations
 Adult
Reproductive function1
 No change
 General observations
 Adult
Respiratory function1
 No change
 General observations
 Adult
Serum lipid levels1
 No change
 Measurement of blood lipids
 Adult
Seizure threshold1
 No change
 Observation of chemically induced seizures
 Adult
Pain or nociception: mechanical1
 No change
 Von frey filament test
 Adult
Pain or nociception: thermal1
 No change
 Tail flick test
 Adult
Aggression1
 No change
 General observations
 Adult
 Not Reported: Circadian sleep/wake cycle, Communications, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Physiological parameters, Repetitive behavior

M_CACNA2D3_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Targeted expression1
Decreased
Description: CACNA2D3 heterozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 allele whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only-Southern blot
 Southern blot
 Adult
Targeted expression1
Decreased
Description: CACNA2D3 heterozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 allele whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only- Western blot
 Western blot
 Adult
Targeted expression1
Decreased
Description: CACNA2D3 heterozygous knockout mice showed reduced endogenous expression together with expression of targetted CACNA2D3 allele whereas wildtype control mice showed endogenous expression only, lacz reporter of the CACNA2D3 targeting allele was expressed in the thalamus, pyramidal cells of the ventro-posterior paraflocculus of the cerebellum, caudate, putamen, the dentate gyrus of the hippocampus, the olfactory bulb and tubercle, and the cortex. CACNA2D3 expression was absent in primary sensory DRG neurons.
Exp Paradigm: Male only- Immunohistochemistry
 Immunohistochemistry
 Adult
Mortality/lethality1
 No change
 Genotypic ratio of progeny from heterozygous parents
 P0
Mortality/lethality1
 No change
 Survival analysis
 P0
Inflammatory response1
 No change
 Local inflammatory reaction
 Adult
Brain morphology1
 No change
 Diffusion tensor imaging (dti)
 Adult
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

 

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