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CEP290
centrosomal protein 290
The CEP290 gene provides instructions for a protein essential for the structure and function of cilia, microscopic cellular projections vital for sensory perception and cell signalling. Pathogenic variants in the CEP290 gene are linked to several inherited conditions, primarily ciliopathies like Leber congenital amaurosis, Joubert syndrome, and Meckel-Gruber syndrome.
CEP290 is located on the long (q) arm of chromosome 12, at band 12q21.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The CEP290 gene contains the blueprint for the centrosomal protein 290. This protein is present in many different cell types, including the light-sensitive cells known as photoreceptors located in the retina. The CEP290 protein forms a crucial part of cellular structures called centrosomes and cilia. Centrosomes are instrumental in cell division and microtubule assembly, while cilia are finger-like projections vital for sensory functions such as vision, hearing, and smell. Proper CEP290 protein function is therefore crucial for maintaining cellular organisation and facilitating transport processes within cells, particularly in the retina.
What the gene does
The CEP290 protein is critical for the proper structure and function of primary cilia, especially within the eye's photoreceptor cells. Photoreceptors have an inner and an outer segment, connected by a cilium. The CEP290 protein helps anchor microtubules within this connecting cilium. This anchoring is essential for regulating the movement of vital proteins and other materials between the segments, which supports the retina's normal structure and function. Furthermore, CEP290 is involved in organising centrosomes, which play a fundamental role in cell division and in forming the microtubule network that gives cells shape and aids intracellular transport. Consequently, impaired CEP290 function can affect various ciliary-dependent biological processes.
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Chromosome location
The CEP290 gene is situated on chromosome 12 at position 12q21.32. This specific chromosomal address is important for understanding the genetic basis of conditions linked to CEP290 variants.
Protein structure
The CEP290 protein is composed of 2479 amino acids and possesses several distinct structural regions. It contains multiple coiled-coil domains located at amino acid positions 59-565, 598-664, 697-931, 958-1027, 1071-1498, 1533-1584, and 1635-2452. The protein also has self-association regions; one from amino acids 1-695 that can associate with itself or its C-terminus, and another from 1966-2479 that can associate with itself or its N-terminus. An interaction site for IQCB1 is found between amino acids 696-896, and disordered regions are present at amino acids 149-168 and 2458-2479.
Key variants
Variants within the CEP290 gene can lead to altered protein function, which may result in various inherited conditions. These changes can affect the protein's ability to maintain ciliary structure and function, impacting several organ systems.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.4024C>T | p.Gln1342Ter | Pathogenic | ★★★☆ | CEP290-related ciliopathy |
c.4438-2A>G | - | Pathogenic | ★★★☆ | CEP290-related ciliopathy |
c.5324dup | p.Asn1775fs | Pathogenic | ★★★☆ | CEP290-related ciliopathy |
c.2268_2284del | p.Asn757_Val758insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.2387_2392delinsTCTTC | p.Lys796fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis |
c.3310-1G>C | - | Pathogenic | ★★☆☆ | Retinal dystrophy |
c.3992del | p.Glu1330_Leu1331insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.5659C>T | p.Gln1887Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis |
c.5750del | p.Lys1917fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome |
c.6417dup | p.Val2140fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the CEP290 gene are associated with a spectrum of inherited disorders known as ciliopathies. These include Leber congenital amaurosis type 10, a severe retinal dystrophy that often presents in infancy, and Joubert syndrome, a complex neurodevelopmental disorder. Additionally, CEP290 variants are linked to Meckel-Gruber syndrome, a lethal developmental disorder characterised by multiple malformations. Senior-Løken syndrome is also associated with CEP290 variants.
Inheritance pattern
Conditions caused by pathogenic CEP290 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The CEP290 gene is included on several NHS Genomic Medicine Service national panels, reflecting its clinical significance in the UK. It is categorised as green for DDG2P, Foetal anomalies (R21), Intellectual disability, Neurological ciliopathies, Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, Renal ciliopathies, Retinal disorders (R32), Skeletal dysplasia (R104), and Structural eye disease (R36), indicating a strong evidence base for its involvement in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
There is no conclusive evidence that specific lifestyle changes can prevent conditions associated with CEP290 gene variants. However, maintaining a healthy lifestyle generally supports overall well-being. Individuals with a genetic diagnosis should discuss any lifestyle considerations with their healthcare provider.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions caused by CEP290 gene variants. Individuals considering supplements should consult with a healthcare professional to discuss potential benefits and risks.
Frequently asked questions
What is the primary role of the CEP290 protein?
The CEP290 protein is crucial for the proper structure and function of cilia, which are microscopic, finger-like projections found on many cell types. It helps in cell division, microtubule assembly, and regulating transport within cells, especially in the eye's photoreceptors.
What conditions are associated with CEP290 gene variants?
Variants in the CEP290 gene are primarily associated with ciliopathies, including Leber congenital amaurosis, Joubert syndrome, and Meckel-Gruber syndrome. These conditions affect various organ systems, often involving the eyes, brain, and kidneys.
How is CEP290 relevant to eye health?
In the eye, the CEP290 protein is vital for the connecting cilium in photoreceptor cells. It helps maintain the structural integrity of these cells and facilitates the transport of essential materials between their inner and outer segments, which is critical for vision.
References
- Moradi P, Davies WL, Mackay DS. Focus on molecules: centrosomal protein 290 (CEP290). Experimental eye research. 2011. PMID: 20493186
- Travaglini L, Brancati F, Attie-Bitach T. Expanding CEP290 mutational spectrum in ciliopathies. American journal of medical genetics. Part A. 2009. PMID: 19764032
- Frank V, den Hollander AI, Brüchle NO. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Human mutation. 2008. PMID: 17705300
- Leitch CC, Zaghloul NA, Davis EE. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nature genetics. 2008. PMID: 18327255
- Brancati F, Barrano G, Silhavy JL. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. American journal of human genetics. 2007. PMID: 17564967
- Baala L, Audollent S, Martinovic J. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. American journal of human genetics. 2007. PMID: 17564974
- Helou J, Otto EA, Attanasio M. Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Løken syndrome. Journal of medical genetics. 2007. PMID: 17617513
- Valente EM, Silhavy JL, Brancati F. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nature genetics. 2006. PMID: 16682970
- Sayer JA, Otto EA, O'Toole JF. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nature genetics. 2006. PMID: 16682973
- den Hollander AI, Koenekoop RK, Yzer S. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. American journal of human genetics. 2006. PMID: 16909394