Capicua (protein)

Structure

Capicua is a highly conserved protein, with a lot of similarity between human and Drosophila melanogaster homologs. In the human body, capicua exists in two isoforms, the short (CIC-S) and the long (CIC-L) one, which differ in their N-terminal section. The two evolutionarily conserved domains of the protein are HMG-box (high-mobility group box) and the C1 domain: they work together to recognize specific octameric DNA sequences. Capicua also contains a nuclear localisation sequence that allows it to enter the nucleus of the cell.

Clinical significance

A new disorder called autosomal dominant intellectual developmental disorder 45 caused by mutations of the CIC gene was first described in 2017.

Spinocerebellar ataxia

Capicua forms a complex with ataxin 1 (CIC-ATXN1 complex) and owing to this interaction it plays a crucial role in the development of spinocerebellar ataxia type 1. While in a healthy organism this complex serves to ensure correct cellular function, in patients with ATXN1 mutations a modified complex has a toxic effect on cerebellar cells, resulting in the motor symptoms typical for this disorder. Blocking the formation of the complex in a murine model of ataxia reduces the symptoms.

Tumors

CIC has been shown to act as a tumor suppressor in numerous types of cancer, and, vice versa, mutations of CIC have been found in some types of tumors. According to a review published in 2020, CIC mutations were most often discovered in oligodendroglioma. A genomic translocation resulting in the formation of a hybrid CIC-DUX4 gene may cause an aggressive Ewing-like sarcoma. Instead of acting as a suppressor, a hybrid protein produced by fusion of CIC and DUX4 has been shown to act as an activator of genes.

According to a review published in 2017, the CIC gene is deleted in 46-53% of analyzed oligodendroglioma tumors as part of the 1p/19q codeletion, a mutation that may also affect the FUBP1 gene.

Ongoing research

According to a study published in 2021, CIC mutations may be among the causes of cerebral folate deficiency.

History

The CIC gene was first identified in Drosophila in 2000. It was shown to encode a transcriptional repressor participating in the regulation of embryogenesis. In a mutated fly which at the embryonic stage had only the first and the last segments present, with the intermediate segments missing, scientists discovered a mutation of the CIC gene, and this prompted them to call the protein capicua ("head-and-tail" in Catalan).

Interactions

• FOLR1 — capicua has been shown to affect the expression of folate receptor alpha, and CIC mutations might result in cerebral folate deficiency.
• ATXN1 — capicua and ataxin 1 form a complex (ATXN1-CIC) which is crucial for proper brain development.
• DUX4 – chimeric CIC-DUX4 proteins are found in tumors.
• FOXO4 – chimeric CIC-FOXO4 proteins are found in tumors.
• NUTM1 – chimeric CIC-NUTM1 proteins are found in tumors.
• LEUTX – chimeric CIC-LEUTX proteins are found in tumors.

References

References

1. (Oct 2002). "CIC, a member of a novel subfamily of the HMG-box superfamily, is transiently expressed in developing granule neurons". Brain Res Mol Brain Res.
2. (Jun 2005). "CIC, a gene involved in cerebellar development and ErbB signaling, is significantly expressed in medulloblastomas". J Neurooncol.
3. "Entrez Gene: CIC capicua transcriptional repressor [ Homo sapiens (human) ]".
4. "Society for Developmental Biology".
5. Lee Y. (2020). "Regulation and function of capicua in mammals.". Exp Mol Med.
6. (April 2017). "Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans". Nature Genetics.
7. (July 2017). "Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases". The American Journal of Surgical Pathology.
8. (April 2020). "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology.
9. (May 2017). "Molecular Testing of Brain Tumor". Journal of Pathology and Translational Medicine.
10. (November 2019). "Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs". Scientific Reports.
11. Cao X, Wolf A, Kim SE, Cabrera RM, Wlodarczyk BJ, Zhu H. (2020). "CIC de novo loss of function variants contribute to cerebral folate deficiency by downregulating FOLR1 expression.". J Med Genet.
12. (March 2017). "A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer". PLOS Genetics.