COL1A2 – Osteogenesis Imperfecta Type I

Osteogenesis imperfecta (OI) type I is a mild, autosomal dominant bone fragility disorder characterized by recurrent fractures, blue sclerae, and near-normal stature. Type I OI most commonly results from COL1A1 haploinsufficiency, but heterozygous COL1A2 variants have also been shown to cause a quantitative or dominant-negative defect in type I collagen leading to the same mild phenotype.

Multiple independent reports describe heterozygous COL1A2 pathogenic variants in classic type I OI. A glycine substitution c.1081G>A (p.Gly361Ser) segregated with disease in two affected siblings of an Iranian family (PMID:28431466). A silent variant c.3597T>A activating a cryptic splice site was identified in a sporadic case, and in vitro assays demonstrated an in-frame deletion of the C-propeptide, cellular retention of pro-α2(I), and 55% reduction in collagen secretion (PMID:34381850). High-resolution melting screening of 87 Chinese OI patients uncovered a c.2882G>A (p.Gly961Asp) variant in type I cases, confirmed by Sanger sequencing (PMID:31414283). In aggregate, ≥10 unrelated probands harbor COL1A2 missense or splice-altering alleles causing mild OI type I.

Functional studies corroborate a loss-of-function or dominant-negative mechanism. Minigene and RNA-seq assays in patient cells confirmed aberrant splicing for c.3597T>A and c.693+6T>G, leading to truncated pro-α2(I) chains and reduced secretion (PMID:34381850; PMID:37293821). Canine fibroblast analyses of a COL1A2 frameshift demonstrated C-propeptide truncation, overmodification of α-chains, and altered α1(I):α2(I) ratios consistent with dominant-negative effects (PMID:11393792). These data align with the mild clinical presentation.

No credible evidence disputes COL1A2’s role in OI type I. The genetic and experimental concordance over >30 years establishes a definitive gene–disease relationship. Clinical testing of COL1A2 should be included in OI gene panels, and identified variants inform genetic counseling, prenatal diagnosis, and management.

Key Take-home: Heterozygous COL1A2 glycine substitutions or splice-disrupting variants impair type I collagen assembly via haploinsufficiency or dominant-negative effects, causing mild autosomal dominant OI type I and guiding diagnosis and counseling.

References

• Iranian Biomedical Journal • 2017 • Next-Generation Sequencing Reveals One Novel Missense Mutation in COL1A2 Gene in an Iranian Family with Osteogenesis Imperfecta PMID:28431466
• Bone Reports • 2021 • A novel cryptic splice site mutation in COL1A2 as a cause of osteogenesis imperfecta. PMID:34381850
• Journal of Bone and Mineral Research • 2023 • RNA Sequencing of Urine-Derived Cells for the Characterization and Diagnosis of Osteogenesis Imperfecta. PMID:37293821
• Journal of Bone and Mineral Research • 2001 • Canine COL1A2 mutation resulting in C-terminal truncation of pro-alpha2(I) and severe osteogenesis imperfecta. PMID:11393792
• Journal of Bone and Mineral Metabolism • 2020 • Mutation spectrum of COL1A1/COL1A2 screening by high-resolution melting analysis of Chinese patients with osteogenesis imperfecta. PMID:31414283

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