# CEP290

## Overview
CEP290 is a gene that encodes the centrosomal protein 290, a crucial component involved in the formation and function of primary cilia. This protein is categorized as a centrosomal protein and plays a significant role in ciliogenesis, acting as a structural and regulatory element at the ciliary transition zone. The protein's structure includes multiple coiled-coil domains and a myosin-tail homology domain, which facilitate its interactions with other proteins and its function in anchoring the ciliary membrane to the microtubule axoneme (Craige2010CEP290; Drivas2013Disruption). Mutations in the CEP290 gene are associated with a variety of ciliopathies, including Leber congenital amaurosis, Joubert syndrome, and Meckel-Gruber syndrome, highlighting its clinical significance in human health (Coppieters2010CEP290; Frank2008Mutations). The protein's interactions with other ciliary components, such as Rab8a and PCM-1, underscore its essential role in maintaining ciliary structure and function (Kim2008CEP290; Tsang2008CP110).

## Structure
CEP290 (centrosomal protein 290) is a large protein integral to ciliary function and centrosome cohesion. Its primary structure includes multiple coiled-coil domains and a myosin-tail homology domain, which are crucial for its interactions and functions (Craige2010CEP290). The N-terminal region of CEP290 contains a conserved amphipathic α-helix motif, essential for membrane binding, while the C-terminal region is involved in microtubule binding (Wu2020CEP290; Drivas2013Disruption). 

The secondary structure of CEP290 likely involves alpha-helices and beta-sheets, contributing to its ability to form a large coiled-coil structure that spans the transition zone of cilia (Craige2010CEP290). The tertiary structure details are less defined, but CEP290's interactions with other proteins suggest a complex quaternary structure, potentially involving the formation of Y-shaped links between microtubules and the ciliary membrane (Potter2021Superresolution).

CEP290 undergoes post-translational modifications, such as phosphorylation, which may regulate its function. The protein also exists in several splice variant isoforms, contributing to its functional diversity and involvement in various cellular processes (Datta2019The). These structural features underscore CEP290's critical role in ciliogenesis and its implications in ciliopathies.

## Function
CEP290 is a critical protein involved in the formation and function of primary cilia, which are essential for cellular signaling and sensory functions in healthy human cells. It plays a pivotal role in ciliogenesis by localizing to the centrosomes and the ciliary transition zone, where it acts as a structural and regulatory element. CEP290 serves as a bridge between the ciliary membrane and the microtubule axoneme, anchoring the ciliary membrane to the axoneme, which is crucial for maintaining the cilium's structure (Drivas2013Disruption).

CEP290 interacts with Rab8a, a small GTPase necessary for cilia assembly, facilitating its recruitment to the centrosome and promoting its entry into the cilium. This interaction is essential for the proper assembly and function of primary cilia (Kim2008CEP290; Tsang2008CP110). CEP290 also interacts with the centriolar satellite component PCM-1, which is involved in microtubule organization and ciliogenesis, indicating its role in maintaining the structure and function of centriolar satellites (Kim2008CEP290).

In photoreceptors, CEP290 is highly expressed and necessary for the proper formation of the connecting cilium, a critical structure for photoreceptor function (Rachel2015CEP290). Its absence or mutation can lead to ciliary defects, resulting in a range of ciliopathies, including vision loss and kidney dysfunction (Rachel2015CEP290).

## Clinical Significance
Mutations in the CEP290 gene are implicated in a range of ciliopathies, which are disorders caused by defects in cilia. One of the most significant conditions associated with CEP290 mutations is Leber congenital amaurosis (LCA), a severe retinal dystrophy leading to blindness or severe visual impairment from birth. The mutation c.2991+1655A>G is a major contributor to LCA, particularly in northwestern Europe (Coppieters2010CEP290; den2006Mutations). CEP290 mutations are also linked to Joubert syndrome (JS), characterized by neurological symptoms and sometimes renal disease, and Meckel-Gruber syndrome (MKS), a lethal multisystemic disorder (Frank2008Mutations; den2006Mutations).

CEP290 is involved in other conditions such as Senior-Loken syndrome (SLS), Bardet-Biedl syndrome (BBS), and cone-rod dystrophy (CORD). These conditions often present with symptoms affecting the retina, kidneys, and neurological systems (Coppieters2010CEP290; Vilaplana2021Clinical). The gene's mutations are mostly nonsense, frameshift, or splice-site changes, leading to a loss of function of the encoded protein, which is crucial for centrosome and cilia structures (Travaglini2009Expanding; Frank2008Mutations). The phenotypic variability associated with CEP290 mutations may be influenced by genetic and environmental factors, as well as interactions with other cilia-associated proteins (Vilaplana2021Clinical).

## Interactions
CEP290 is a centrosomal protein that plays a critical role in ciliary function and interacts with various proteins to form multiprotein complexes. It interacts with the centriolar satellite component PCM-1, which is essential for its recruitment to centriolar satellites. This interaction is dependent on microtubules, as disruption of the microtubule network affects CEP290's localization (Kim2008CEP290). CEP290 also interacts with BBS4 at centriolar satellites, contributing to protein recruitment and microtubule organization. It is involved in the formation of the BBSome, a complex containing BBS proteins and PCM-1, potentially in a catalytic manner involving ATP binding (Kim2008CEP290).

CEP290 interacts with Rab8a, a small GTPase necessary for cilia assembly, and this interaction is crucial for recruiting Rab8a to the centrosome, which is essential for ciliogenesis (Tsang2008CP110). The interaction between CEP290 and CP110 is significant, as CP110 suppresses primary cilia formation through its binding to CEP290. This interaction is necessary for CP110's ability to inhibit cilia assembly (Tsang2008CP110).

In the retina, CEP290 associates with RPGR and other proteins, participating in common functional pathways. It is part of multiprotein complexes with centrosomal and microtubule-associated proteins, including RPGRIP1 and dynactin subunits (Chang2006Inframe).


## References


[1. (Wu2020CEP290) Zhimao Wu, Nan Pang, Yingying Zhang, Huicheng Chen, Ying Peng, Jingyan Fu, and Qing Wei. Cep290 is essential for the initiation of ciliary transition zone assembly. PLOS Biology, 18(12):e3001034, December 2020. URL: http://dx.doi.org/10.1371/journal.pbio.3001034, doi:10.1371/journal.pbio.3001034. This article has 37 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1371/journal.pbio.3001034)

[2. (Vilaplana2021Clinical) Ferran Vilaplana, Andrea Ros, Belen Garcia, Ignacio Blanco, Elisabeth Castellanos, Nicholas John Edwards, Xavier Valldeperas, Susana Ruiz-Bilbao, and Antonio Sabala. Clinical characteristics, imaging findings, and genetic results of a patient with cep290-related cone-rod dystrophy. Ophthalmic Genetics, 42(4):474–479, April 2021. URL: http://dx.doi.org/10.1080/13816810.2021.1916827, doi:10.1080/13816810.2021.1916827. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/13816810.2021.1916827)

[3. (Chang2006Inframe) Bo Chang, Hemant Khanna, Norman Hawes, David Jimeno, Shirley He, Concepcion Lillo, Sunil K. Parapuram, Hong Cheng, Alison Scott, Ron E. Hurd, John A. Sayer, Edgar A. Otto, Massimo Attanasio, John F. O’Toole, Genglin Jin, Chengchao Shou, Friedhelm Hildebrandt, David S. Williams, John R. Heckenlively, and Anand Swaroop. In-frame deletion in a novel centrosomal/ciliary protein cep290/nphp6 perturbs its interaction with rpgr and results in early-onset retinal degeneration in the rd16 mouse. Human Molecular Genetics, 15(11):1847–1857, April 2006. URL: http://dx.doi.org/10.1093/hmg/ddl107, doi:10.1093/hmg/ddl107. This article has 288 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddl107)

[4. (den2006Mutations) Anneke I. den Hollander, Robert K. Koenekoop, Suzanne Yzer, Irma Lopez, Maarten L. Arends, Krysta E.J. Voesenek, Marijke N. Zonneveld, Tim M. Strom, Thomas Meitinger, Han G. Brunner, Carel B. Hoyng, L. Ingeborgh van den Born, Klaus Rohrschneider, and Frans P.M. Cremers. Mutations in the cep290 (nphp6) gene are a frequent cause of leber congenital amaurosis. The American Journal of Human Genetics, 79(3):556–561, September 2006. URL: http://dx.doi.org/10.1086/507318, doi:10.1086/507318. This article has 500 citations.](https://doi.org/10.1086/507318)

[5. (Coppieters2010CEP290) Frauke Coppieters, Steve Lefever, Bart P. Leroy, and Elfride De Baere. Cep290, a gene with many faces: mutation overview and presentation of cep290base. Human Mutation, 31(10):1097–1108, August 2010. URL: http://dx.doi.org/10.1002/humu.21337, doi:10.1002/humu.21337. This article has 235 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.21337)

[6. (Craige2010CEP290) Branch Craige, Che-Chia Tsao, Dennis R. Diener, Yuqing Hou, Karl-Ferdinand Lechtreck, Joel L. Rosenbaum, and George B. Witman. Cep290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. Journal of Cell Biology, 190(5):927–940, September 2010. URL: http://dx.doi.org/10.1083/jcb.201006105, doi:10.1083/jcb.201006105. This article has 329 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1083/jcb.201006105)

[7. (Drivas2013Disruption) Theodore G. Drivas, Erika L.F. Holzbaur, and Jean Bennett. Disruption of cep290 microtubule/membrane-binding domains causes retinal degeneration. Journal of Clinical Investigation, 123(10):4525–4539, September 2013. URL: http://dx.doi.org/10.1172/jci69448, doi:10.1172/jci69448. This article has 66 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci69448)

[8. (Datta2019The) Poppy Datta, Brandon Hendrickson, Sarah Brendalen, Avri Ruffcorn, and Seongjin Seo. The myosin-tail homology domain of centrosomal protein 290 is essential for protein confinement between the inner and outer segments in photoreceptors. Journal of Biological Chemistry, 294(50):19119–19136, December 2019. URL: http://dx.doi.org/10.1074/jbc.ra119.009712, doi:10.1074/jbc.ra119.009712. This article has 24 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.ra119.009712)

[9. (Tsang2008CP110) William Y. Tsang, Carine Bossard, Hemant Khanna, Johan Peränen, Anand Swaroop, Vivek Malhotra, and Brian David Dynlacht. Cp110 suppresses primary cilia formation through its interaction with cep290, a protein deficient in human ciliary disease. Developmental Cell, 15(2):187–197, August 2008. URL: http://dx.doi.org/10.1016/j.devcel.2008.07.004, doi:10.1016/j.devcel.2008.07.004. This article has 217 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.devcel.2008.07.004)

[10. (Potter2021Superresolution) Valencia L. Potter, Abigail R. Moye, Michael A. Robichaux, and Theodore G. Wensel. Super-resolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein cep290. JCI Insight, October 2021. URL: http://dx.doi.org/10.1172/jci.insight.145256, doi:10.1172/jci.insight.145256. This article has 19 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1172/jci.insight.145256)

[11. (Rachel2015CEP290) Rivka A. Rachel, Erin A. Yamamoto, Mrinal K. Dewanjee, Helen L. May-Simera, Yuri V. Sergeev, Alice N. Hackett, Katherine Pohida, Jeeva Munasinghe, Norimoto Gotoh, Bill Wickstead, Robert N. Fariss, Lijin Dong, Tiansen Li, and Anand Swaroop. Cep290 alleles in mice disrupt tissue-specific cilia biogenesis and recapitulate features of syndromic ciliopathies. Human Molecular Genetics, 24(13):3775–3791, April 2015. URL: http://dx.doi.org/10.1093/hmg/ddv123, doi:10.1093/hmg/ddv123. This article has 103 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddv123)

[12. (Frank2008Mutations) Valeska Frank, Anneke I. den Hollander, Nadina Ortiz Brüchle, Marijke N. Zonneveld, Gudrun Nürnberg, Christian Becker, Gabriele Du Bois, Heide Kendziorra, Susanne Roosing, Jan Senderek, Peter Nürnberg, Frans P.M. Cremers, Klaus Zerres, and Carsten Bergmann. Mutations of thecep290gene encoding a centrosomal protein cause meckel-gruber syndrome. Human Mutation, 29(1):45–52, January 2008. URL: http://dx.doi.org/10.1002/humu.20614, doi:10.1002/humu.20614. This article has 110 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.20614)

[13. (Kim2008CEP290) Joon Kim, Suguna Rani Krishnaswami, and Joseph G. Gleeson. Cep290 interacts with the centriolar satellite component pcm-1 and is required for rab8 localization to the primary cilium. Human Molecular Genetics, 17(23):3796–3805, September 2008. URL: http://dx.doi.org/10.1093/hmg/ddn277, doi:10.1093/hmg/ddn277. This article has 251 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddn277)

[14. (Travaglini2009Expanding) Lorena Travaglini, Francesco Brancati, Tania Attie‐Bitach, Sophie Audollent, Enrico Bertini, Josseline Kaplan, Isabelle Perrault, Miriam Iannicelli, Brunella Mancuso, Luciana Rigoli, Jean‐Michel Rozet, Dominika Swistun, Jerlyn Tolentino, Bruno Dallapiccola, Joseph G. Gleeson, and Enza Maria Valente. Expanding cep290 mutational spectrum in ciliopathies. American Journal of Medical Genetics Part A, 149A(10):2173–2180, September 2009. URL: http://dx.doi.org/10.1002/ajmg.a.33025, doi:10.1002/ajmg.a.33025. This article has 34 citations.](https://doi.org/10.1002/ajmg.a.33025)