Autosomal-recessive "founder" mutations in the CC2D1A gene were identified in 4 families with a total of 16 individuals affected by a spectrum of cognitive and social impairments, including ASD, non-syndromic ID, and seizures (Manzini et al., 2014).
Molecular Function
This gene encodes a transcriptional repressor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. Performs an essential function in controlling the functional maturation of synapses. Mutations in this gene are associated with mental retardation, autosomal recessive 3 (MRT3) [MIM:608443], a non-syndromic disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
CC2D1A regulates human intellectual and social function as well as NF-B signaling homeostasis.
Ccd2d1a null mice die very soon after birth, recapitulated in different constructs developed in different laboratories. The cause of death is failure to breathe and impaired swallowing even if overall the newborn pups do not display any major anatomical defect in the heart, lung or brain. Ccd2d1a conditional knockout from forebrain excitatory neurons specifically results in mice that survive through adulthood and are fertile. These conditional knockouts display several behavioral impairments including poor spatial learning, excessive self-grooming, hyperactivity, increased anxiety and deficiencies in social approach and communication.
References
Type
Title
Author, Year
Primary
Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The targeting construct constains engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter. These two elements are flanked by FRT sites in intron 11 of Cc2d1a. The loxP sites flank exons 12-14. Authors note that t.
Allele Type: Gene trapped
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: C57BL/6
Mutant ES Cell Line: Model Source: Knockout mouse project repository (ID 49663)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To avert early mortality of Cc2d1a null pups, the gene trapped mice were bred on to several backgrounds including 129/SvEvTac and Swiss Webster.
Allele Type: Gene trapped
Strain of Origin: Genetic Background: 129Sv/EvTac
ES Cell Line: Mutant ES Cell Line: Model Source: 26826102
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To avert early mortality of Cc2d1a null pups, the gene trapped mice were bred on to several backgrounds including 129/SvEvTac and Swiss Webster.
Allele Type: Gene trapped
Strain of Origin: Genetic Background: Swiss Webster
ES Cell Line: Mutant ES Cell Line: Model Source: 26826102
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 12-14 of the Cc2d1a (gene- trapped construct) using Camk11-cre, in excitatory neurons of the forebrain. A reporter line Thy1-YFP-H was crossed with the cKO to visualize dendritic architecture.
Allele Type: Conditional loss-of-function
Strain of Origin: 129Sv/EvTac
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: 26826102
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 12-14 of the Cc2d1a (gene- trapped construct) using Nestin-cre,in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL/6 * 129SvEvTac
ES Cell Line: Mutant ES Cell Line: Model Source: 26826102
Model Type:
Genetic
Model Genotype:
Homozygous; heterozygous
Mutation:
Cc2d1a homozygous/Cc2d1b heterozygous mice were generated by crossing Cc2d1a homozygous with Cc2d1b heterozygous mice. Cc2d1a null mouse line (KO) generated by the Knockout Mouse Project Repository (Project Design ID 49663), with targeted construct containing engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter, both elements flanked by FRT sites in intron 11 of Cc2d1a. Cc2d1b heterozygous mice were bred from a Cc2d1b null mouse line (KO) generated by the Knockout Mouse Project Repository (Project ID CDS 34981) as a gene-trap allele inserted in intron 2 of Cc2d1b.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Knockout Mouse Project Repository
Model Type:
Genetic
Model Genotype:
Heterozygous; heterozygous
Mutation:
Cc2d1a/1b double heterozygous mice were generated by crossing Cc2d1a heterozygotes with Cc2d1b heterozygotes. Cc2d1a heterozygous mice were bred from a Cc2d1a null mouse line (KO) generated by the Knockout Mouse Project Repository (Project Design ID 49663), with targeted construct containing engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter, both elements flanked by FRT sites in intron 11 of Cc2d1a. Cc2d1b heterozygous mice were bred from a Cc2d1b null mouse line (KO) generated by the Knockout Mouse Project Repository (Project ID CDS 34981) as a gene-trap allele inserted in intron 2 of Cc2d1b.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Knockout Mouse Project Repository
Model Type:
Genetic
Model Genotype:
Homozygous; homozygous
Mutation:
Cc2d1a/1b double null mice were generated by crossing Cc2d1a null mouse line (KO) generated by the Knockout Mouse Project Repository (Project Design ID 49663), with targeted construct containing engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter, both elements flanked by FRT sites in intron 11 of Cc2d1a, and Cc2d1b null mouse line (KO) generated by the Knockout Mouse Project Repository (Project ID CDS 34981) as a gene-trap allele inserted in intron 2 of Cc2d1b.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Knockout Mouse Project Repository
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Cc2d1a heterozygous mice were generated by crossing Cc2d1a null mouse line (KO) generated by the Knockout Mouse Project Repository (Project Design ID 49663), with targeted construct containing engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter, both elements flanked by FRT sites in intron 11 of Cc2d1a, into wildtype C57BL/6 background.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Knockout Mouse Project Repository
Model Type:
Genetic
Model Genotype:
Heterozygous; homozygous
Mutation:
Cc2d1a heterozygous/Cc2d1b homozygous mice were generated by crossing Cc2d1a heterozygotes with Cc2d1b homozygous mice. Cc2d1a heterozygous mice were bred from a Cc2d1a null mouse line (KO) generated by the Knockout Mouse Project Repository (Project Design ID 49663), with targeted construct containing engrailed 2 splice acceptor (EN2SA) gene-trap allele with bicistronic expression of beta-galactosidase and a neo cassette under the human beta-actin promoter, both elements flanked by FRT sites in intron 11 of Cc2d1a. Cc2d1b null mouse line (KO) generated by the Knockout Mouse Project Repository (Project ID CDS 34981) as a gene-trap allele inserted in intron 2 of Cc2d1b.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source: Knockout Mouse Project Repository
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: Histology
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: General observations
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: Histology
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: General observations
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: Histology
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: General observations
Description: A significant reduction in spine density is observed in the trunk and barrel fields of the somatosensory cortex in cc2d1a cko mice
Exp Paradigm: NA
Description: Cc2d1a cko males have reduced nose-to-body contact with females that the authors note maybe indicative of mating behavior
Exp Paradigm: NA
Description: Cc2d1a cko mice have longer latencies to find the hidden platform compared to wt in the initial days of trial, however their latency reduces (performance improves) significantly over the trial days to catch up with wt
Exp Paradigm: Males only
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: Histology
Description: Cc2d1a ko pups have severe breathing problems at birth(following cesarean delivery), with 25% of them not breathing at all. in some pups ingested milk is aspirated into the lungs
Exp Paradigm: General observations
Description: Cc2d1a/cc2d1b double mutants showed reduced actual percentage of birthed pups compared to the expected percentage of birthed pups compared to controls.
Exp Paradigm: NA
Description: Cc2d1a/cc2d1b double heterozygous male mutants showed an increase in distance traveled in open field test compared to controls.
Exp Paradigm: NA
Description: Cc2d1a/cc2d1b double heterozygous male mutants showed an increase in exploratory activity of objects compared to controls.
Exp Paradigm: NA
Description: Cc2d1a/cc2d1b double heterozygous male mutants showed a decrease in time spent in the center of open field compared to controls.
Exp Paradigm: NA
Description: Cc2d1a/cc2d1b double heterozygous mutants showed a decrease in time exploring the novel object during the 15-min nort test compared to controls.
Exp Paradigm: NA
Description: Cc2d1a/cc2d1b double heterozygous mutants showed a decrease in time spent in the hidden platform quadrant of the probe trial compared to controls. this effect was evident in the first 15 seconds of a 60-second trial but not in the whole trial overall.
Exp Paradigm: Probe task
Description: Cc2d1a/cc2d1b double heterozygous male mutants showed a decrease in spatial learning (manifested in increased latency to reach the hidden platform) compared to controls.
Exp Paradigm: Latency to reach hidden platform
Description: Cc2d1a/cc2d1b double knockout mutants showed increased emryonic lethality compared to controls. all mutants died mid-gestation before e11.5, when the embryo was found almost entirely absent.
Exp Paradigm: NA
