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.
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
