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CRB1
crumbs cell polarity complex component 1
The CRB1 gene provides instructions for a protein essential for normal vision, particularly in the development and function of the retina's light-sensing cells. The CRB1 gene encodes the crumbs cell polarity complex component 1 protein, which is vital for the proper arrangement of photoreceptors and maintaining cell polarity within the retina.
CRB1 is located on the long (q) arm of chromosome 1, at band 1q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The CRB1 gene, or crumbs cell polarity complex component 1, is crucial for normal visual function. It provides the genetic blueprint for a protein predominantly found in the retina, the light-sensitive tissue at the back of the eye. This protein is integral to the proper development and organisation of retinal cells, particularly the light-sensing photoreceptors.
Disruptions to the CRB1 gene's function can lead to various inherited retinal diseases, which often result in significant vision impairment.
What the gene does
The protein produced from the CRB1 gene is a key component in maintaining the structural integrity and cellular organisation of the retina. It is thought to be part of a protein complex that helps establish cell polarity within photoreceptors, ensuring that their various components are correctly positioned. This precise arrangement is fundamental for the photoreceptors to effectively detect light and colour.
Beyond cell polarity, the CRB1 protein may also facilitate the formation of connections between different types of cells within the retina, which is essential for signal transmission and overall retinal function. Its role in the normal development of photoreceptors highlights its importance for maintaining healthy vision.
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Chromosome location
The CRB1 gene is situated on the long arm of chromosome 1, specifically at position 1q31.3. This location defines the gene's physical address within the human genome, providing a reference point for genetic studies and diagnostic analyses.
Protein structure
The CRB1 protein is composed of 1406 amino acids and features a complex domain architecture. It includes multiple EGF-like domains: EGF-like 1 (amino acids 30-68), EGF-like 2 (70-108), EGF-like 3 (110-146), EGF-like 4; calcium-binding (148-184), EGF-like 5; calcium-binding (186-222), EGF-like 6; calcium-binding (224-260), EGF-like 7; calcium-binding (262-299), EGF-like 8 (301-337), EGF-like 9 (339-395), EGF-like 10; calcium-binding (397-439), EGF-like 11 (441-481), EGF-like 12 (672-708), and EGF-like 13 (887-923). Additionally, it contains two Laminin G-like domains: Laminin G-like 1 (485-670) and Laminin G-like 2 (714-885). These domains are crucial for the protein's interactions and its role in cellular structure and signalling.
Key variants
Pathogenic variants within the CRB1 gene are responsible for a spectrum of inherited retinal disorders. These genetic changes can affect the protein's structure or function, leading to impaired retinal development and function. Different types of variants, including missense, nonsense, and frameshift mutations, can be associated with varying disease severity and clinical presentation.
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.1244T>A | p.Leu415Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinal dystrophy |
c.1478del | p.Phe493fs | Pathogenic | ★★☆☆ | Leber congenital amaurosis 8 |
c.1623C>A | p.Tyr541Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 12 |
c.1690G>T | p.Asp564Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Pigmented paravenous retinochoroidal atrophy |
c.2129-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 12 |
c.2129-2A>G | - | Pathogenic | ★★☆☆ | Pigmented paravenous retinochoroidal atrophy |
c.2536G>T | p.Gly846Ter | Pathogenic | ★★☆☆ | Retinal dystrophy |
c.2815T>G | p.Cys939Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 8 |
c.2881del | p.Ile961fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 8 |
c.3429C>A | p.Cys1143Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 12 |
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
Variants in the CRB1 gene are linked to several inherited conditions primarily affecting the retina. These include Leber congenital amaurosis (type 8), a severe form of early-onset vision loss, and cone-rod dystrophy, which progressively impairs both central and peripheral vision. The gene is also associated with retinitis pigmentosa, a group of disorders causing progressive degeneration of photoreceptors and the retinal pigment epithelium.
No disease links recorded for this gene in our reference set.
UK clinical status
The CRB1 gene is recognised within the NHS Genomic Medicine Service, being listed on both the DDG2P and Retinal disorders (R32) panels. This inclusion indicates its established clinical relevance for genetic testing in the UK for developmental disorders and inherited retinal conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the CRB1 gene responsible for?
The CRB1 gene provides instructions for making a protein that is critical for normal vision. It plays a key role in the development and proper arrangement of light-sensing photoreceptor cells within the retina.
What conditions are associated with variants in the CRB1 gene?
Pathogenic variants in the CRB1 gene are associated with several inherited retinal disorders, including Leber congenital amaurosis (type 8), cone-rod dystrophy, and retinitis pigmentosa. These conditions typically lead to vision impairment.
How does the CRB1 protein function in the eye?
The CRB1 protein helps establish cell polarity in photoreceptors, ensuring their components are correctly positioned. It also contributes to the connections between different retinal cells, supporting overall retinal structure and function.
References
- Gosens I, den Hollander AI, Cremers FP. Composition and function of the Crumbs protein complex in the mammalian retina. Experimental eye research. 2008. PMID: 18407265
- den Hollander AI, Roepman R, Koenekoop RK. Leber congenital amaurosis: genes, proteins and disease mechanisms. Progress in retinal and eye research. 2008. PMID: 18632300
- Richard M, Roepman R, Aartsen WM. Towards understanding CRUMBS function in retinal dystrophies. Human molecular genetics. 2006. PMID: 16987889
- van de Pavert SA, Kantardzhieva A, Malysheva A. Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. Journal of cell science. 2004. PMID: 15316081
- den Hollander AI, Davis J, van der Velde-Visser SD. CRB1 mutation spectrum in inherited retinal dystrophies. Human mutation. 2004. PMID: 15459956
- Jacobson SG, Cideciyan AV, Aleman TS. Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Human molecular genetics. 2003. PMID: 12700176
- Lotery AJ, Jacobson SG, Fishman GA. Mutations in the CRB1 gene cause Leber congenital amaurosis. Archives of ophthalmology (Chicago, Ill. : 1960). 2001. PMID: 11231775
- den Hollander AI, Heckenlively JR, van den Born LI. Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. American journal of human genetics. 2001. PMID: 11389483
- den Hollander AI, ten Brink JB, de Kok YJ. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nature genetics. 1999. PMID: 10508521