CRTAP – Osteogenesis Imperfecta Type VII

CRTAP is associated with autosomal recessive osteogenesis imperfecta type VII (MONDO:0012536). To date, three unrelated probands have been reported: one male fetus harboring a deep intronic c.794-1403A>G variant leading to cryptic exon inclusion and two patients from distinct nonconsanguineous families with biallelic splice-site mutations (c.621+1G>A; c.1153-3C>G) causing CRTAP deficiency (PMID:37146916, PMID:38214665). No additional segregating affected relatives have been documented.

Functional studies demonstrate that mutant CRTAP transcripts yield unstable isoforms with a ‘GWxxI’ degron, resulting in loss of prolyl 3-hydroxylation of type I collagen, intracellular collagen aggregation, impaired osteoblast proliferation, severe generalized osteoporosis, and lethal cellular senescence (PMID:37146916, PMID:38214665). This mechanistic concordance supports a pathogenic loss-of-function mechanism. These findings have direct implications for molecular diagnosis, genetic counseling, and potential therapeutic targeting of collagen hydroxylation pathways.

Key take-home: Biallelic CRTAP loss-of-function variants cause severe osteogenesis imperfecta type VII by disrupting collagen 3-hydroxylation and stability, warranting inclusion of CRTAP in diagnostic gene panels for early-onset OI.

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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