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CRTAP
cartilage associated protein
The *CRTAP* gene provides instructions for making a protein crucial for bone formation and mineralisation, and variants in this gene are linked to certain forms of osteogenesis imperfecta. The *CRTAP* gene, or cartilage associated protein gene, plays a vital role in skeletal development, particularly influencing bone quality and strength.
CRTAP is located on the short (p) arm of chromosome 3, at band 3p22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The *CRTAP* gene encodes a protein known as cartilage associated protein, which is integral to the normal development and maintenance of bone tissue [PMID:17940562]. This protein is part of a complex that helps regulate collagen post-translational modification, a process essential for bone matrix integrity. Disruptions in *CRTAP* function can lead to severe skeletal disorders, most notably osteogenesis imperfecta.
Inherited in an autosomal recessive pattern, conditions linked to *CRTAP* typically require pathogenic variants in both copies of the gene for symptoms to manifest. Understanding the role of *CRTAP* is important for diagnosing and managing associated bone fragility disorders [PMID:19129528].
What the gene does
The protein encoded by the *CRTAP* gene is localised to the endoplasmic reticulum and forms part of a molecular complex with LEPRE1 and PPIB proteins. This complex is responsible for modifying type I collagen, the most abundant protein in bone and connective tissues [PMID:17940562]. Specifically, CRTAP helps to hydroxylate proline residues on collagen chains, a critical step for collagen's proper folding, stability, and extracellular assembly.
Effective collagen cross-linking and fibril formation are dependent on these modifications, which directly impact bone mineralisation and overall mechanical strength. When the CRTAP protein is non-functional or deficient due to gene variants, collagen processing is impaired, leading to fragile bones and other connective tissue abnormalities characteristic of osteogenesis imperfecta.
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Chromosome location
The *CRTAP* gene is situated on the long arm of chromosome 3 at position 3p22.3. This specific genomic location provides the cellular machinery with the blueprint for synthesising the cartilage associated protein.
Protein structure
The CRTAP protein consists of 401 amino acid residues. Domain architecture has not been experimentally characterised in detail for this protein, although it is known to interact with other proteins like LEPRE1 and PPIB within a larger complex essential for collagen modification.
Key variants
Variants within the *CRTAP* gene encompass a range of genetic changes, including single nucleotide substitutions, small insertions, and deletions. Such changes can alter the amino acid sequence of the CRTAP protein, modify gene expression, or lead to a truncated protein. Pathogenic variants typically result in a loss of normal protein function, impacting its critical role in collagen processing and bone development.
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.1020C>G | p.Tyr340Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.153_175dup | p.His59fs | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.198C>A | p.Tyr66Ter | Pathogenic | ★★☆☆ | Osteogenesis imperfecta |
c.288del | p.Ala97fs | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.320_321del | p.Arg107fs | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.404del | p.Ser135fs | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.444C>G | p.Tyr148Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.634C>T | p.Arg212Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.731_732del | p.Leu244fs | Pathogenic/Likely pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
c.822_826delinsT | p.Lys274fs | Pathogenic | ★★☆☆ | Osteogenesis imperfecta type 7 |
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 *CRTAP* gene are primarily associated with certain forms of osteogenesis imperfecta. This inherited condition is characterised by extreme bone fragility, leading to frequent fractures, short stature, and bone deformities [PMID:19129528]. Individuals with *CRTAP*-related osteogenesis imperfecta often present with severe symptoms due to the integral role of the CRTAP protein in maintaining bone matrix integrity. The inheritance pattern for this condition is autosomal recessive.
Inheritance pattern
Conditions caused by pathogenic CRTAP variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The *CRTAP* gene is assessed by the UK's NHS Genomic Medicine Service. It is listed on several Green panels, indicating strong evidence for its association with human disease and its utility in genetic testing. These panels include Foetal anomalies (R21), Osteogenesis imperfecta (R102), and Skeletal dysplasia (R104).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the CRTAP gene?
The *CRTAP* gene provides instructions for making the cartilage associated protein, which is essential for the proper formation and mineralisation of bones. It works as part of a complex to modify type I collagen, a key structural protein in bone.
What condition is associated with variants in the CRTAP gene?
Pathogenic variants in the *CRTAP* gene are primarily associated with certain types of osteogenesis imperfecta, an inherited disorder characterised by fragile bones and increased susceptibility to fractures.
How is osteogenesis imperfecta related to the CRTAP gene inherited?
Osteogenesis imperfecta linked to *CRTAP* variants follows an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the *CRTAP* gene, one from each parent, to develop the condition.