Alternative titles; symbols
HGNC Approved Gene Symbol: CIC
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:42,268,530-42,295,796 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Intellectual developmental disorder, autosomal dominant 45 | 617600 | Autosomal dominant | 3 |
The CIC gene encodes a transcriptional repressor that interacts with ATXN1 (601556) (summary by Lu et al., 2017).
By sequencing cloned obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) obtained a partial CIC clone, which they designated KIAA0306. The deduced 1,451-amino acid sequence shows weak homology with the mouse HMG-box transcription factor Sox18 (601618). RT-PCR analysis revealed ubiquitous CIC expression.
Lee et al. (2002) identified CIC in both human and mouse genomes using database mining to identify SOX (see 602148)-related genes. The human cDNA predicted a 1,608-amino acid protein. Human and mouse genes exhibit 92% identity, with 100% identity in the HMG domain. Because the level of similarity of CIC to other SOX genes is insufficient for inclusion as a genuine member of the SOX subfamily, CIC represents a new member of a SOX-related HMG subfamily. RT-PCR of developing mouse central nervous system showed that Cic is highly expressed in the developing mouse brain, particularly in the immature granular cells in the cerebellum, hippocampus, and olfactory bulb.
Because Drosophila Cic had been shown to mediate c-erbB (EGFR; see 131550) signaling via transcriptional repression, Lee et al. (2005) studied the expression of human CIC in medulloblastoma, where high levels of ERBB2 (164870) and ERBB4 (600543) correlate with poor prognosis. In silico SAGE analysis of human normal and malignant brain demonstrated that medulloblastoma exhibited the highest level of CIC expression and that expression was most common in tumors of the central nervous system in general. RT-PCR and in situ hybridization verified the expression of CIC in tumor cells, although the level of expression varied between different medulloblastoma subtypes. In mouse postnatally developing cerebellum, in silico analysis and in situ hybridization indicated a strong correlation between Cic expression and the maturation profile of cerebellar granule cell precursors.
Lam et al. (2006) examined soluble protein complexes from mouse cerebellum and found that the majority of wildtype and expanded Atxn1 (601556) assembles into large stable complexes containing the transcriptional repressor Cic. Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady-state level of Cic. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1, substantially reduced the association of mutant Atxn1 with Cic in vivo. Lam et al. (2006) concluded that their data provided insight into the function of Atxn1 and suggested that the neuropathology of SCA1 (164400), caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions. Lam et al. (2006) found that the majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino acid sequence conserved across species.
Lim et al. (2008) demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. Lim et al. (2008) concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.
Using whole-genome sequencing to identify genes involved in high-altitude adaptation in 2 ethnically distinct groups of Ethiopian highlanders living at 3,500 meters above sea level on Bale Plateau or Chennek field in Ethiopia, Udpa et al. (2014) identified regions with significant loss of diversity, including a region on chromosome 19 that contains 8 genes, including CIC, LIPE (151750), and PAFAH1B3 (603074). The authors evaluated the roles of these genes in hypoxia tolerance by using small interfering RNA in Drosophila. Knockdown of Cic, Hsl, or Pafaha, the fly orthologs of CIC, LIPE, and PAFAH1B3, respectively, resulted in increased tolerance and survival in hypoxic environments. Udpa et al. (2014) concluded that these genes may encode evolutionarily conserved proteins involved in hypoxia tolerance.
Lee et al. (2002) determined that the CIC gene contains 20 exons.
Using a radiation hybrid panel, Nagase et al. (1997) mapped the CIC gene to chromosome 19. Lee et al. (2002) mapped the human CIC gene to chromosome 19q13.2.
Intellectual Developmental Disorder, Autosomal Dominant 45
In 5 patients from 4 unrelated families with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Lu et al. (2017) identified 4 different heterozygous truncating or frameshift mutations in the CIC gene (612082.0001-612082.0004). All mutations occurred de novo, although 1 patient inherited the mutation from his unaffected father who was mosaic for the mutant allele, and 2 affected sibs likely inherited the mutation from an unaffected parent who was gonadal mosaic. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Cells derived from 1 patient showed a 50% decrease in mRNA and protein levels, consistent with haploinsufficiency.
In a boy with MRD45, Vissers et al. (2010) identified a heterozygous de novo missense mutation (R292W; 612082.0005) in the CIC gene.
Somatic Mutations
Bettegowda et al. (2011) performed exonic sequencing of 7 oligodendrogliomas (see 137800). Among other changes, they found that the CIC gene on chromosome 19q was somatically mutated in 6 cases and that the FUBP1 (603444) gene on chromosome 1p was somatically mutated in 2 tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. Bettegowda et al. (2011) concluded that their results suggested a critical role for these genes in the biology and pathology of oligodendrocytes.
In 2 cases of Ewing-like sarcomas (see 612219), Kawamura-Saito et al. (2006) identified the chromosomal translocation t(4;19)(q35;q13). The breakpoint at chromosome 19q13 was within exon 20 of the CIC gene, and the breakpoint at chromosome 4q35 was within the DUX4 (606009) coding region in the D4Z4 repeat region. The translocation resulted in a CIC-DUX4 fusion transcript that was translated into a chimeric protein containing most of the CIC sequence, including the HMG box and TLE (see 600189)-binding sites, fused in frame to the C terminus of DUX4. The chimeric protein did not contain the N-terminal DNA-binding homeodomains of DUX4. No reciprocal DUX4-CIC transcripts were observed. The CIC-DUX4 transcript induced anchorage-independent growth when transfected into mouse fibroblasts. Although CIC is a transcriptional repressor, the CIC-DUX4 transcript enhanced transcription of a reporter gene when transfected into HeLa cells. Microarray analysis revealed altered gene expression following transfection of CIC-DUX4 into a human osteosarcoma cell line, including significantly upregulated expression of ERM (ETV5; 601600) and ETV1 (600541). Chromatin immunoprecipitation analysis and electrophoretic mobility shift assays confirmed binding of the chimeric protein to the ERM and ETV1 promoters.
Studies of the pathogenesis of SCA1 supported a model in which the expanded glutamine tract in the ATXN1 gene causes toxicity by modulating the normal activities of that gene. To explore native interactions that modify the toxicity of ATXN1, Bowman et al. (2007) generated a targeted duplication of the mouse Ataxn1l gene (614301), a highly conserved paralog of Atxn1, and tested the role of this protein in SCA1 pathology. Using a knockin mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, Bowman et al. (2007) found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua. The results provided genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and underscored the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.
Lu et al. (2017) found that conditional knockdown of the Cic gene in the mouse developing forebrain causing learning and memory deficits and hyperactivity that responded to low-dose amphetamine. Conditional knockout mice had decreased cortical thickness of layers 2 to 4, apparently due to increased apoptosis, as well as decreased dendritic branching compared to controls. These changes were associated with a decrease in CUX1 (116896) levels. Cortical layers 5 and 6 were not decreased, but there was decreased thickness of the hippocampal dentate gyrus. The overall findings suggested a defect in postnatal maturation or maintenance of upper-layer cortical neurons.
In a girl with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Lu et al. (2017) identified a heterozygous de novo c.1057C-T transition (c.1057C-T, NM_015125.4) in the CIC gene, resulting in an arg353-to-ter (R353X) substitution. Patient cells showed a 50% reduction in mRNA and protein, indicating that the mutation results in nonsense-mediated mRNA decay and a loss of function consistent with haploinsufficiency. The mutation was found by exome sequencing and confirmed by Sanger sequencing.
In 2 sibs with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Lu et al. (2017) identified a heterozygous 8-bp duplication (c.1801_1808dupAAGAGACC, NM_015125.4) in the CIC gene, resulting in a frameshift and premature termination (Glu604ArgfsTer127). The mutation occurred de novo in the patients, with presumed gonadal mosaicism in 1 of the unaffected parents. The mutation was found by exome sequencing and confirmed by Sanger sequencing.
In a 4-year-old boy with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Lu et al. (2017) identified a de novo heterozygous c.2571_2587delinsC mutation (c.2571_2587delinsC, NM_015125.4) in the CIC gene, resulting in a frameshift and premature termination (Thr859AlafsTer63). The mutation was found by exome sequencing and confirmed by Sanger sequencing.
In a 15-year-old boy with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Lu et al. (2017) identified a de novo heterozygous c.2974C-T transition (c.2974C-T, NM_015125.4) in the CIC gene, resulting in a gln992-to-ter (Q992X) substitution. The mutation was inherited from the unaffected father who was mosaic for the mutant allele (15% mosaicism). The mutation was found by exome sequencing and confirmed by Sanger sequencing.
In a boy (MR Trio 6) with autosomal dominant intellectual developmental disorder-45 (MRD45; 617600), Vissers et al. (2010) identified a heterozygous de novo c.1474C-T transition (c.1474C-T, NM_015125) in the CIC gene, resulting in an arg492-to-trp (R492W) substitution. No functional studies were performed.
Bettegowda, C., Agrawal, N., Jiao, Y., Sausen, M., Wood, L. D., Hruban, R. H., Rodriguez, F. J., Cahill, D. P., McLendon, R., Riggins, G., Velculescu, V. E., Oba-Shinjo, S. M., Marie, S. K. N., Vogelstein, B., Bigner, D., Yan, H., Papadopoulos, N., Kinzler, K. W. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333: 1453-1455, 2011. [PubMed: 21817013] [Full Text: https://doi.org/10.1126/science.1210557]
Bowman, A. B., Lam, Y. C., Jafar-Nejad, P., Chen, H.-K., Richman, R., Samaco, R. C., Fryer, J. D., Kahle, J. J., Orr, H. T., Zoghbi, H. Y. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nature Genet. 39: 373-379, 2007. [PubMed: 17322884] [Full Text: https://doi.org/10.1038/ng1977]
Kawamura-Saito, M., Yamazaki, Y., Kaneko, K., Kawaguchi, N., Kanda, H., Mukai, H., Gotoh, T., Motoi, T., Fukayama, M., Aburatani, H., Takizawa, T., Nakamura, T. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum. Molec. Genet. 15: 2125-2137, 2006. [PubMed: 16717057] [Full Text: https://doi.org/10.1093/hmg/ddl136]
Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., Zoghbi, H. Y. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127: 1335-1347, 2006. [PubMed: 17190598] [Full Text: https://doi.org/10.1016/j.cell.2006.11.038]
Lee, C.-J., Chan, W.-I., Cheung, M., Cheng, Y.-C., Appleby, V. J., Orme, A. T., Scotting, P. J. CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons. Molec. Brain Res. 106: 151-156, 2002. [PubMed: 12393275] [Full Text: https://doi.org/10.1016/s0169-328x(02)00439-4]
Lee, C.-J., Chan, W.-I., Scotting, P. J. CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas. J. Neurooncol. 73: 101-108, 2005. [PubMed: 15981098] [Full Text: https://doi.org/10.1007/s11060-004-4598-2]
Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., Zoghbi, H. Y. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452: 713-718, 2008. [PubMed: 18337722] [Full Text: https://doi.org/10.1038/nature06731]
Lu, H.-C., Tan, Q., Rousseaux, M. W. C., Wang, W., Kim, J.-Y., Richman, R., Wan, Y.-W., Yeh, S.-Y., Patel, J. M., Liu, X., Lin, T., Lee, Y., and 25 others. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nature Genet. 49: 527-536, 2017. [PubMed: 28288114] [Full Text: https://doi.org/10.1038/ng.3808]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Udpa, N., Ronen, R., Zhou, D., Liang, J., Stobdan, T., Appenzeller, O., Yin, Y., Du, Y., Guo, L., Cao, R., Wang, Y., Jin, X., and 15 others. Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol. 15: R36, 2014. Note: Electronic Article. [PubMed: 24555826] [Full Text: https://doi.org/10.1186/gb-2014-15-2-r36]
Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B. W. M., Hoischen, A., de Vries, B. B. A., Brunner, H. G., Veltman, J. A. A de novo paradigm for mental retardation. Nature Genet. 42: 1109-1112, 2010. [PubMed: 21076407] [Full Text: https://doi.org/10.1038/ng.712]