A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.
Molecular Function
The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. It may play a role in development of the central nervous system.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Selective Emx1-Cre mediated deletion of CIC in the developing mouse forebrain results in behavioral abnormalities including increased exploratory activities, decreased anxiety and decreased cued and contextual fear conditioning. Low-dose amphetamine treatment calmed the Cic conditional knockout mice. Histological abnormalities in the brain include reduced thickness of cortical layers 24 together with a decrease in the number of SATB2 and CUX1 positive cells and SATB2-CUX1 co-expressing cells in layer 2-4 postnatally, between birth and 5 weeks of age. Cortical layers 5 and 6 are not reduced in thickness and do not show a change in CTIP2 positive cells. Selective Neurod6-Cre mediated deletion of CIC in postmitotic excitatory neurons of the developing mouse forebrain also showed reduction of SATB2 and CUX1 in cortical layers 2-4. Selective Emx1-Cre mediated deletion of CIC in the developing mouse forebrain also results in reduced dendritic complexity of pyramidal neurons in cortical layers 2-4 but not in layers 5-6. Selective Opt-Cre mediated deletion of Cic in the hypothalamus and medial amygdala results in abnormal social behavior including reduced social approach in the three-chambered test, reduced interaction with a novel mouse in the partition test and increased aggression in the resident-intruder test, although exploratory activity was not affected (Lu HC, Nat. Gen, 2017).
References
Type
Title
Author, Year
Primary
Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with a heterozygous null allele for CIC.
Allele Type: Targeted
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of Cic using Emx1-Cre in the neurons and glia of the neocortex, hippompus and pallium, E10.5 onwards
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of critical exons located between position 25287449 and 25289896 (chromosome 7) of Cic using Emx1-Cre in the neurons and glia of the neocortex, hippompus and pallium, E10.5 onwards. The floxed mice were developed in the KOMP project
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion o of critical exons located between position 25287449 and 25289896 (chromosome 7) of Cic using Neurod6-Cre or(Nex-cre) in the postmitotic excitatory neurons of the forebrain. The floxed mice were developed by the KOMP
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of critical exons located between position 25287449 and 25289896 (chromosome 7) of Cic using OTP-cre (orthopedia homeobox) in the medial amygdala, hypothalamic regions including paraventricular nucleus, supraoptic nucleus and lateral hypothalamic area, dorsomedial and ventromedial nuclei
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of critical exons located between position 25287449 and 25289896 (chromosome 7) of Cic using OTP-Cre (orthopedia homeobox)in the medial amygdala, hypothalamic regions including paraventricular nucleus, supraoptic nucleus and lateral hypothalamic area, dorsomedial and ventromedial nuclei
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Mutants show decreased dendritic branching of pyramidal neurons in layers 2 and 3 of the cerebral cortex but show no change in branching of pyramidal neurons in layers 5 and 6 of the cerebral cortex, compared to controls.
Exp Paradigm: Neurons were labeled with injection of low-titre aav-yfp at p0.
Description: Mutants show decreased thickness of layers 2 and 3 but normal thinkness of layers 5 and 6 of the cerebral cortex, compared to controls.
Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show decreased neuronal numbers in layers 2 and 3 but normal neuronal numbers in layers 5 and 6 of the cerebral cortex, compared to controls. in mutants, layers 2 and 3 specific neuronal markers (satb2 and cux1) were reduced but a layers 5 and 6 specific marker (ctip2) were not changed, compared to controls (5 weeks). mutants showed no change in cux1 and satb2 positive cells in layers 2 and 3 of the cortex at p0, comapared to controls but the cux1 and satb2 neuronal numbers declined at p5 and p10.
Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show a decrease in satb2 and cux1 double positive cells, compared to controls, indicating a disruption in lamina specific cell types.
Exp Paradigm: NA
Description: Mutants show decreased thickness of the dentate gyrus of the hippocampus but no change in the thickness of the ca1 and ca3 regions, compared to controls.
Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls.
Exp Paradigm: Western blot
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls.
Exp Paradigm: Immunohistochemistry
Description: Mutants show decreased neuronal numbers in layers 2 and 3 but normal neuronal numbers in layers 5 and 6 of the cerebral cortex, compared to controls.
Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show a decrease in social interaction in the partition test measured by a decrease in time spent with the novel mouse, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased expression of cic in cre expressing cells in the paraventricular nucleus (pvn), ventromedial hypothalamus (vmh), arcuate nucleus (arc), and medial amygdala (mea), compared to controls.
Exp Paradigm: NA
Description: Mutants show abnormal gene expression in opt lineage neurons with 123 genes upregulated and 84 genes downregulated, compared to controls. a few genes in this subset were validated using qrt-pcr.
Exp Paradigm: Translating ribosome affinity purification (trap) approach was performed using the cre-dependent rosafstrap mouse line.-gene expression microarray
Description: Mutants show abnormal gene expression in opt lineage neurons with 123 genes upregulated and 84 genes downregulated, compared to controls. a few genes in this subset were validated using qrt-pcr.
Exp Paradigm: Translating ribosome affinity purification (trap) approach was performed using the cre-dependent rosafstrap mouse line.- quantitative pcr (qrt-pcr)
Description: Mutants show a decrease in social interaction in the partition test measured by a decrease in time spent with the novel mouse, compared to controls.
Exp Paradigm: NA
Description: Mutants show decreased expression of cic in cre expressing cells in the paraventricular nucleus (pvn), ventromedial hypothalamus (vmh), arcuate nucleus (arc), and medial amygdala (mea), compared to controls.
Exp Paradigm: NA
