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CRB2
crumbs cell polarity complex component 2
The *CRB2* gene provides instructions for a protein involved in maintaining cell polarity and integrity, particularly important in kidney development and function. The *CRB2* gene encodes the crumbs cell polarity complex component 2 protein, which is crucial for establishing and maintaining cell organisation.
CRB2 is located on the long (q) arm of chromosome 9, at band 9q33.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The *CRB2* gene, also known as crumbs cell polarity complex component 2, plays a fundamental role in organising cells and tissues within the body. Its protein product contributes to the formation of epithelial cell junctions and polarity, which are vital for the proper function of organs, especially the kidneys. Dysfunction of the *CRB2* gene has been implicated in a spectrum of inherited disorders affecting renal and neurological systems.
What the gene does
The protein encoded by *CRB2* is a key component of the Crumbs complex, an evolutionarily conserved protein complex that regulates epithelial cell polarity, adhesion, and differentiation. It helps to define the apical surface of epithelial cells, which is crucial for barrier function and directional transport in tissues like the kidney. Beyond its general role in cell polarity, the CRB2 protein is also required for maximum inhibition of APP amyloid-beta peptide secretion, suggesting a potential role in other cellular processes. Abnormalities in this gene can disrupt the elaborate cellular architecture required for normal organ development and function.
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Chromosome location
The *CRB2* gene is found on chromosome 9, specifically at band 9q33.3. This chromosomal location indicates where the gene resides within the human genome, providing a reference point for genetic studies and diagnostic investigations.
Protein structure
The CRB2 protein is composed of 1285 amino acids and features a complex domain architecture. Its N-terminal region, spanning amino acids 1-350, is notably required for maximum inhibition of APP amyloid-beta peptide secretion. Within this region and extending further, are ten EGF-like domains: EGF-like 1 (amino acids 67-106), EGF-like 2 (amino acids 108-144), EGF-like 3 (amino acids 146-182), EGF-like 4 (amino acids 184-221), EGF-like 5 (amino acids 223-259), EGF-like 6 (amino acids 261-318), EGF-like 7 (amino acids 320-356), EGF-like 8 (amino acids 358-394), EGF-like 9 (amino acids 396-436), and EGF-like 10 (amino acids 605-641). Several of these EGF-like domains (2, 3, 4, 7, 8) are described as calcium-binding. Additionally, the protein contains three Laminin G-like domains: Laminin G-like 1 (amino acids 431-603), Laminin G-like 2 (amino acids 647-805), and Laminin G-like 3 (amino acids 871-1054).
Key variants
Variations within the *CRB2* gene can include single nucleotide changes, insertions, or deletions that alter the gene's sequence. These changes may lead to a non-functional or improperly functioning protein, impacting its ability to maintain cell polarity and contribute to normal development. The clinical significance of any identified variant needs careful evaluation, often in the context of an individual's symptoms and family history.
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.2277G>A | p.Trp759Ter | Pathogenic | ★★☆☆ | not provided |
c.2400C>G | p.Asn800Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Familial idiopathic steroid-resistant nephrotic syndrome |
c.2445_2446del | p.Cys816fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.3089_3104del | p.Arg1030fs | Pathogenic/Likely pathogenic | ★★☆☆ | CRB2-related disorder |
c.3089_3104dup | p.Gly1036fs | Pathogenic/Likely pathogenic | ★★☆☆ | Focal segmental glomerulosclerosis 9 |
c.315C>A | p.Cys105Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ventriculomegaly-cystic kidney disease |
c.3291_3292del | p.Cys1098fs | Pathogenic | ★★☆☆ | CRB2-related disorder |
c.3613G>A | p.Gly1205Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Focal segmental glomerulosclerosis 9 |
c.592dup | p.Thr198fs | Pathogenic/Likely pathogenic | ★★☆☆ | Focal segmental glomerulosclerosis 9 |
c.823C>T | p.Arg275Ter | Pathogenic | ★★☆☆ | Ventriculomegaly-cystic kidney disease |
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 *CRB2* gene are typically associated with conditions inherited in an autosomal recessive manner. These conditions primarily affect the kidneys and brain, falling under the broader category of ciliopathies. Such disorders can lead to issues with renal function, structural abnormalities, and neurological developmental challenges.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic CRB2 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 *CRB2* gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is included on diagnostic panels for DDG2P, Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability (R29), Neurological ciliopathies, Proteinuric renal disease (R195), Rare multisystem ciliopathy disorders, and Renal ciliopathies, all categorised as green for their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the typical inheritance pattern for conditions linked to the *CRB2* gene?
Conditions associated with pathogenic variants in the *CRB2* gene are generally inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
Which organs are primarily affected by *CRB2* gene variants?
Pathogenic variants in the *CRB2* gene predominantly affect the kidneys and the brain. Related conditions often manifest with issues in renal function and neurological development.
What is cell polarity and why is it important for the *CRB2* gene?
Cell polarity refers to the biochemical and structural differences between the ends of a cell, which is essential for cells to perform specialised functions. The *CRB2* gene's protein product is crucial for establishing and maintaining this polarity, especially in epithelial cells, ensuring organs like the kidneys can function correctly.