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Relevance to Autism

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
ASD
Support
Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.
ASD
Support
A de novo paradigm for mental retardation.
ID
Support
Recent ultra-rare inherited variants implicate new autism candidate risk genes
ASD
Support
Utility of clinical exome sequencing in a complex Emirati pediatric cohort
ASD, DD
Recent Recommendation
Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.
DD, ID
ASDor autistic features, epilepsy/seizures
Recent Recommendation
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN882R001 
 stop_gained 
 c.820C>T 
 p.Arg274Ter 
 De novo 
 NA 
 Simplex 
 GEN882R002 
 missense_variant 
 c.457C>T 
 p.Pro153Ser 
 De novo 
 NA 
 Simplex 
 GEN882R003 
 stop_gained 
 c.1582C>T 
 p.Arg528Ter 
 De novo 
 NA 
 Simplex 
 GEN882R004 
 stop_gained 
 c.673C>T 
 p.Arg225Cys 
 Familial 
  
 Simplex 
 GEN882R005 
 missense_variant 
 c.1474C>T 
 p.Arg492Trp 
 De novo 
 NA 
 Simplex 
 GEN882R006 
 stop_gained 
 c.1057C>T 
 p.Arg353Ter 
 De novo 
 NA 
 Simplex 
 GEN882R007 
 frameshift_variant 
 c.4528_4535dup 
 p.Glu1513ArgfsTer127 
 De novo 
 NA 
 Multiplex (presumed germline mosaicism) 
 GEN882R008 
 frameshift_variant 
 c.2571_2578delinsC 
 p.Thr859AlafsTer63 
 De novo 
 NA 
 Simplex 
 GEN882R009 
 stop_gained 
 c.2864C>T 
 p.Pro955Leu 
 Familial 
 Paternal 
 Simplex 
 GEN882R010 
 frameshift_variant 
 c.774_783del 
 p.Pro259ValfsTer88 
 De novo 
 NA 
 Simplex 
 GEN882R011 
 missense_variant 
 c.1927G>C 
 p.Gly643Arg 
 Unknown 
  
 Multiplex 
 GEN882R012 
 frameshift_variant 
 c.4143del 
 p.Asp1382ThrfsTer26 
 Familial 
  
 Simplex 
 GEN882R013 
 frameshift_variant 
 c.6796del 
 p.Glu2266SerfsTer58 
 Familial 
  
 Simplex 
 GEN882R014 
 stop_gained 
 c.7480C>T 
 p.Gln2494Ter 
 Familial 
  
 Simplex 
 GEN882R015 
 stop_gained 
 c.3547C>T 
 p.Arg1183Ter 
 Familial 
  
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion
 1
 
19
Duplication
 1
 
19
Deletion
 5
 

Model Summary

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.

M_CIC_1_KO_HT

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:

M_CIC_2_CKO_HM

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:

M_CIC_2_CKO_HT

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:

M_CIC_4_CKO_HM

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:

M_CIC_5_CKO_HM

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:

M_CIC_5_CKO_HT

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:

M_CIC_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hyperactivity1
Increased
Description: Mutants show an increase in total distance travelled compared to controls.
Exp Paradigm: NA
 Open field test
 12-13 weeks
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 16-20 weeks
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 16-20 weeks
Object recognition memory1
 No change
 Novel object recognition test
 NA
Social approach1
 No change
 Three-chamber social approach test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory

M_CIC_2_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
Description: Mutants show increase in total distance travelled and in the speed of locomotion compared to controls.
Exp Paradigm: NA
 Open field test
 12-13 weeks
Dendritic architecture: dendritic tree complexity1
Decreased
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.
 Sholl analysis
 5 weeks
Cortical thickness1
Decreased
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.
 Immunohistochemistry
 5, 20 weeks
Neuronal number1
Decreased
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.
 Immunohistochemistry
 P0, p5, p10, 5, 20 weeks
Cortical lamination1
Decreased
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
 Immunohistochemistry
 Unreported
Hippocampal morphology1
Decreased
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.
 Immunohistochemistry
 20 weeks
Presynaptic function: paired-pulse facilitation1
Increased
Description: Mutants show increase in paired-pulse ratio compared to controls.
Exp Paradigm: NA
 Paired-pulse ratio
 Unreported
Apoptosis: brain cells1
Increased
Description: Mutants show increased caspase3 staining in layers 2 and 4 of the cerebral cortex, compared to controls.
Exp Paradigm: NA
 Expression of cleaved caspase-3 (cc3)
 P5, p10
Anxiety1
Decreased
Description: Mutants show increase in time spent in open arms compared to controls.
Exp Paradigm: NA
 Elevated plus maze test
 12-13 weeks
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Mutants show decreased freezing in response to the cue of fear conditioning compared to controls.
Exp Paradigm: NA
 Fear conditioning test
 16-20 weeks
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Mutants show decreased freezing in response to the context of fear conditioning compared to controls.
Exp Paradigm: NA
 Fear conditioning test
 16-20 weeks
Gene expression1
Decreased
Description: Mutants show decreased expression of cux1 but not cux2 mrna in layers 2-4 of the cerebral cortex compared to controls.
Exp Paradigm: NA
 In situ hybridization (ish)
 Unreported
Targeted expression1
Decreased
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls.
Exp Paradigm: Western blot
 Western blot
 Unreported
Targeted expression1
Decreased
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls.
Exp Paradigm: Immunohistochemistry
 Immunohistochemistry
 Unreported
Gene expression1
Increased
Description: Mutants show increased gene expression of etv1,4,5, that are known to be repressed by cic, compared to controls.
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 Unreported
Protein expression level evidence1
 No change
 Western blot
 Unreported
Cell proliferation: neural precursors1
 No change
 Immunohistochemistry
 E14,5, e16.5
Hippocampal morphology1
 No change
 Immunohistochemistry
 5 weeks
Morphology and size of the corpus callosum1
 No change
 Histology
 Unreported
Morphology of the amygdala1
 No change
 Immunohistochemistry
 5, 20 weeks
Neuronal differentiation1
 No change
 NA
 E14,5, e16.5
Epsp-spike relationship1
 No change
 Field potential recordings
 Unreported
Synaptic plasticity: hippocampal ltp1
 No change
 Field potential recordings
 Unreported
Social approach1
 No change
 Three-chamber social approach test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Physiological parameters, Repetitive behavior, Seizure, Sensory

M_CIC_2_CKO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Gene expression1
Increased
Description: Mutants show increased gene expression of etv1,4,5, that are known to be repressed by cic, compared to controls.
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 Unreported
Targeted expression1
Decreased
Description: Mutants show decreased expression of cic in all cortical layers compared to controls.
Exp Paradigm: NA
 Immunohistochemistry
 Unreported
Anxiety1
 No change
 Elevated plus maze test
 12-13 weeks
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 16-20 weeks
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 16-20 weeks
General locomotor activity: ambulatory activity1
 No change
 Open field test
 12-13 weeks
Cortical thickness1
 No change
 Histology
 5, 20 weeks
Hippocampal morphology1
 No change
 Immunohistochemistry
 5 weeks
Morphology of the amygdala1
 No change
 Immunohistochemistry
 5, 20 weeks
Neuronal number1
 No change
 Immunohistochemistry
 5 weeks
Epsp-spike relationship1
 No change
 Field potential recordings
 Unreported
Presynaptic function: paired-pulse facilitation1
 No change
 Paired-pulse ratio
 Unreported
Synaptic plasticity: hippocampal ltp1
 No change
 Field potential recordings
 Unreported
Social approach1
 No change
 Three-chamber social approach test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Physiological parameters, Repetitive behavior, Seizure, Sensory

M_CIC_4_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal number1
Decreased
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.
 Immunohistochemistry
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_CIC_5_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Aggression1
Increased
Description: Mutants show increase in the number and duration of attacks compared to controls.
Exp Paradigm: NA
 Resident-intruder test
 Unreported
Social interaction1
Decreased
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
 Partition test
 Unreported
Social approach1
Decreased
Description: Mutants show decreased interaction time with a stranger mouse over an object, compared to controls
Exp Paradigm: NA
 Three-chamber social approach test
 Unreported
Gene expression1
Abnormal
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)
 Quantitative pcr (qrt-pcr)
 8-10 weeks
Targeted expression1
Decreased
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
 Immunohistochemistry
 Unreported
Gene expression1
Abnormal
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
 Gene expression microarray
 8-10 weeks
Anxiety1
 No change
 Elevated plus maze test
 12-13 weeks
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 16-20 weeks
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 16-20 weeks
Hyperactivity1
 No change
 Open field test
 12-13 weeks
Hypothalamic morphology1
 No change
 Immunohistochemistry
 Unreported
Morphology of the amygdala1
 No change
 Immunohistochemistry
 Unreported
Neuronal number: neuroendocrine cells1
 No change
 Immunohistochemistry
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory

M_CIC_5_CKO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Social interaction1
Decreased
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
 Partition test
 Unreported
Social approach1
Decreased
Description: Mutants show decreased interaction time with a stranger mouse over an object, compared to controls
Exp Paradigm: NA
 Three-chamber social approach test
 Unreported
Targeted expression1
Decreased
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
 Immunohistochemistry
 Unreported
Anxiety1
 No change
 Elevated plus maze test
 12-13 weeks
Cued or contextual fear conditioning: memory of context1
 No change
 Fear conditioning test
 16-20 weeks
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 16-20 weeks
General locomotor activity: ambulatory activity1
 No change
 Open field test
 12-13 weeks
Aggression1
 No change
 Resident-intruder test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory

 

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