CEP290

Last updated
CEP290
Identifiers
Aliases CEP290 , 3H11Ag, BBS14, CT87, JBTS5, LCA10, MKS4, NPHP6, POC3, SLSN6, rd16, centrosomal protein 290
External IDs OMIM: 610142 MGI: 2384917 HomoloGene: 77213 GeneCards: CEP290
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_025114

NM_146009
NM_001400997

RefSeq (protein)

NP_079390

NP_666121
NP_001387926

Location (UCSC) Chr 12: 88.05 – 88.14 Mb Chr 10: 100.32 – 100.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene. [5] [6] [7] [8] CEP290 is located on the Q arm of chromosome 12.

Contents

Function

The gene CEP290 is a centrosomal protein that plays an important role in centrosome and cilia development. This gene is vital in the formation of the primary cilium, a small antenna-like projections of the cell membrane that plays an important role in the photoreceptors at the back of the retina (which detect light and color) and in the kidney, brain, and many other organs of the body. Knocking down levels of the CEP290 gene transcript resulted in dramatic suppression of ciliogenesis in retinal pigment epithelial cells in culture, proving just how important CEP290 is to cilia formation.

On a molecular level, CEP290 has been shown to play a critical regulatory and structural role in primary cilium formation. Recent studies have implicated CEP290 as a microtubule and membrane binding protein that might serve as a structural link between the microtubule core of the cilium and the overlying ciliary membrane. [9] Disruption of CEP290's microtubule binding domain in the rd16 mouse model of CEP290 disease [7] has been shown to result in rapid and dramatic retinal degeneration, demonstrating the importance of CEP290 microtubule binding in disease. The role of CEP290 in promoting ciliogenesis is inhibited both by auto-regulatory domains found at either end of the CEP290 protein [9] and through CEP290's interaction with the inhibitory protein CP110. [10]

The discovery of the CEP290 gene has led researchers to find another gene critical in retinal function, LCA5. Clinical trials involving gene replacement of these two genes have started in Philadelphia, where researchers are hopeful that Leber Congenital Amaurosis will one day be cured. [11] [12] [13]

Structure

This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. [8]

Clinical significance

Mutations in this gene have been associated with Joubert syndrome and nephronophthisis, and recently with a frequent form of Leber's congenital amaurosis, called LCA10. The presence of antibodies against this protein is associated with several forms of cancer. [8]

A mutation in this gene leads to infant and child blindness, a disease known as Leber Congenital Amaurosis. As of today, 35 different mutations in CEP290 are responsible for causing LCA. Other mutations in CEP290 have also been identified in causing Meckel Syndrome and Joubert Syndrome, a few among many syndromes. A defective CEP290 gene is usually the cause of these disorders due to abnormal cilia. It is unknown how one mutation in a gene can cause so many different types of syndromes, particularly many of which affect the Central Nervous System.

Related Research Articles

<span class="mw-page-title-main">Cilium</span> Organelle found on eukaryotic cells

The cilium, plural cilia, is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projection that extends from the surface of the much larger cell body. Eukaryotic flagella found on sperm cells and many protozoans have a similar structure to motile cilia that enables swimming through liquids; they are longer than cilia and have a different undulating motion.

<span class="mw-page-title-main">Basal body</span> Protein structure found at the base of cilium or flagellum).

A basal body is a protein structure found at the base of a eukaryotic undulipodium. The basal body was named by Theodor Wilhelm Engelmann in 1880 It is formed from a centriole and several additional protein structures, and is, essentially, a modified centriole. The basal body serves as a nucleation site for the growth of the axoneme microtubules. Centrioles, from which basal bodies are derived, act as anchoring sites for proteins that in turn anchor microtubules, and are known as the microtubule organizing center (MTOC). These microtubules provide structure and facilitate movement of vesicles and organelles within many eukaryotic cells.

Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.

<span class="mw-page-title-main">Intraflagellar transport</span>

Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface. Plasmodium falciparum cilia and the sperm flagella of Drosophila are examples of cilia that assemble in the cytoplasm and do not require IFT. The process of IFT involves movement of large protein complexes called IFT particles or trains from the cell body to the ciliary tip and followed by their return to the cell body. The outward or anterograde movement is powered by kinesin-2 while the inward or retrograde movement is powered by cytoplasmic dynein 2/1b. The IFT particles are composed of about 20 proteins organized in two subcomplexes called complex A and B.

<span class="mw-page-title-main">Senior–Løken syndrome</span> Congenital eye disorder

Senior–Løken syndrome is a congenital eye disorder, first characterized in 1961. It is a rare, ciliopathic, autosomal recessive disorder characterized by juvenile nephronophthis and progressive eye disease.

<span class="mw-page-title-main">Retinitis pigmentosa GTPase regulator</span> Protein-coding gene in the species Homo sapiens

X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene. The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.

<span class="mw-page-title-main">CRB1</span> Protein-coding gene in the species Homo sapiens

Crumbs homolog 1 is a protein that in humans is encoded by the CRB1 gene.

<span class="mw-page-title-main">AIPL1</span> Protein-coding gene in the species Homo sapiens

Aryl-hydrocarbon-interacting protein-like 1 is a protein that in humans is encoded by the AIPL1 gene.

<span class="mw-page-title-main">PCNT</span> Protein-coding gene in the species Homo sapiens

Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21. This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression. This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome.

<span class="mw-page-title-main">RPGRIP1</span> Protein-coding gene in the species Homo sapiens

X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 is a protein in the ciliary transition zone that in humans is encoded by the RPGRIP1 gene. RPGRIP1 is a multi-domain protein containing a coiled-coil domain at the N-terminus, two C2 domains and a C-terminal RPGR-interacting domain (RID). Defects in the gene result in the Leber congenital amaurosis (LCA) syndrome and in the eye disease glaucoma.

<span class="mw-page-title-main">INVS</span> Protein-coding gene in the species Homo sapiens

Inversin is a protein that in humans is encoded by the INVS gene.

<span class="mw-page-title-main">RDH12</span> Protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 12 is an enzyme that in humans is encoded by the RDH12 gene.

<span class="mw-page-title-main">NPHP4</span> Protein-coding gene in the species Homo sapiens

Nephrocystin-4 is a protein that in humans is encoded by the NPHP4 gene.

Conorenal syndrome, is a collection of medical conditions that seem to have a common genetic cause.

<span class="mw-page-title-main">DNAH11</span> Protein-coding gene in the species Homo sapiens

Dynein heavy chain 11, axonemal is a protein that in humans is encoded by the DNAH11 gene.

<span class="mw-page-title-main">LCA5</span> Protein-coding gene in the species Homo sapiens

Lebercilin, also known as leber congenital amaurosis 5 (LCA5), is a protein that in humans is encoded by the LCA5 gene. This protein is thought to be involved in centrosomal or ciliary functions.

RPGRIP1L is a human gene.

<span class="mw-page-title-main">CC2D2A</span> Protein-coding gene in the species Homo sapiens

Coiled-coil and C2 domain-containing protein 2A that in humans is encoded by the CC2D2A gene.

<span class="mw-page-title-main">ARL13B</span> Protein-coding gene in the species Homo sapiens

ADP-ribosylation factor-like protein 13B (ARL13B), also known as ADP-ribosylation factor-like protein 2-like 1, is a protein that in humans is encoded by the ARL13B gene.

Ciliogenesis is defined as the building of the cell's antenna or extracellular fluid mediation mechanism. It includes the assembly and disassembly of the cilia during the cell cycle. Cilia are important organelles of cells and are involved in numerous activities such as cell signaling, processing developmental signals, and directing the flow of fluids such as mucus over and around cells. Due to the importance of these cell processes, defects in ciliogenesis can lead to numerous human diseases related to non-functioning cilia. Ciliogenesis may also play a role in the development of left/right handedness in humans.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198707 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019971 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Guo J, Jin G, Meng L, Ma H, Nie D, Wu J, Yuan L, Shou C (Oct 2004). "Subcellullar localization of tumor-associated antigen 3H11Ag". Biochem Biophys Res Commun. 324 (2): 922–30. doi:10.1016/j.bbrc.2004.09.133. PMID   15474516.
  6. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F (May 2006). "The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4". Nat Genet. 38 (6): 674–81. doi:10.1038/ng1786. PMID   16682973. S2CID   16941062.
  7. 1 2 Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, Parapuram SK, Cheng H, Scott A, Hurd RE, Sayer JA, Otto EA, Attanasio M, O'Toole JF, Jin G, Shou C, Hildebrandt F, Williams DS, Heckenlively JR, Swaroop A (May 2006). "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". Hum Mol Genet. 15 (11): 1847–57. doi:10.1093/hmg/ddl107. PMC   1592550 . PMID   16632484.
  8. 1 2 3 "Entrez Gene: CEP290 centrosomal protein 290kDa".
  9. 1 2 Drivas TG, Holzbaur EL, Bennett J (Oct 2013). "Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration". J Clin Invest. 123 (10): 4525–39. doi:10.1172/JCI69448. PMC   3784542 . PMID   24051377.
  10. Tsang WY, Bossard C, Khanna H, Peränen J, Swaroop A, Malhotra V, Dynlacht BD (Aug 2008). "CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease". Dev Cell. 15 (2): 187–97. doi:10.1016/j.devcel.2008.07.004. PMC   3987787 . PMID   18694559.
  11. Kniffin, Cassandra L. "OMIM Entry Centrosomal Protein 290-KD." Archived 2011-10-26 at the Wayback Machine N.p., 24 May 2006. Web. 30 Mar. 2013.
  12. "Genetics Home Reference Gene CEP290." . US National Library of Medicine, 25 Mar. 2013. Web. 30 Mar. 2013.
  13. McGill University Health Centre. "Gene Responsible For Blindness In Infants And Children Identified." ScienceDaily, 4 Jun. 2007. Web. 30 Mar. 2013.

Further reading