CRTAP – Osteogenesis Imperfecta Type III

CRTAP (cartilage-associated protein) encodes a core component of the prolyl 3-hydroxylation complex required for type I collagen maturation. Biallelic CRTAP variants result in an autosomal recessive, severe deforming osteogenesis imperfecta phenotype corresponding to MONDO_0009804 (type III). The overall clinical validity is categorized as Moderate given multiple unrelated probands with loss-of-function alleles and concordant experimental data supporting collagen dysregulation.

Genetic evidence includes three unrelated affected individuals from two families harboring biallelic CRTAP splice‐site variants: c.621+1G>A (PMID:38214665) and c.1153-3C>G (PMID:38214665), as well as a deep intronic c.794-1403A>G variant producing aberrant CRTAP transcripts (PMID:37146916). No additional segregation beyond index cases has been reported. These variants predict loss of CRTAP function through aberrant splicing or transcript instability.

Functional studies demonstrate that mutant CRTAP transcripts undergo nonsense‐mediated decay or encode unstable isoforms, leading to significant reduction in CRTAP mRNA and protein in patient osteoblasts. Prolyl 3-hydroxylation at α1(I)Pro986 is markedly decreased, resulting in type I collagen aggregation and impaired bone matrix formation in vitro (PMID:37146916; PMID:38214665). These findings confirm a loss‐of‐function mechanism consistent with the patient phenotype.

No published studies have disputed the association of CRTAP with severe OI type III. The available data integrate genetic and experimental lines of evidence linking CRTAP deficiency to defective collagen post-translational modification and the characteristic severe deforming phenotype.

In summary, CRTAP fulfills criteria for a Moderate gene–disease association with autosomal recessive inheritance, specific loss‐of‐function variants, and functional assays demonstrating pathogenicity.

Key Take-home: CRTAP biallelic loss-of-function variants impair collagen 3-hydroxylation and cause severe autosomal recessive OI type III, supporting diagnostic genetic testing and functional follow-up.

References

• Biochimica et biophysica acta. Molecular basis of disease • 2023 • Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII PMID:37146916
• The Journal of clinical endocrinology and metabolism • 2024 • Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants PMID:38214665

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