COL1A2 – Osteogenesis Imperfecta Type II

COL1A2 encodes the pro-alpha2(I) chain of type I collagen, a critical triple-helical fibrillar collagen in bone. Osteogenesis imperfecta type II is a perinatal lethal skeletal dysplasia characterised by extreme bone fragility, intrauterine fractures and absent calvarial mineralization. Prenatal ultrasound and computed tomography can detect long bone deformities and skull hypomineralization by 13–14 weeks of gestation (Sonography at 13 wk; 3D-CT at 20 wk) ([PMID:8415424], [PMID:23181495]).

Genetic evidence includes three unrelated probands with heterozygous glycine substitution mutations in the COL1A2 triple-helix domain, each presenting with lethal OI type II ([PMID:8415424], [PMID:23181495], [PMID:1284475]). De novo occurrence is supported by absence of these variants in parental genomic DNA except for somatic mosaicism in one father. No additional multiplex family segregation has been reported.

Inheritance is autosomal dominant, with recurrence risk elevated in cases of parental mosaicism but negligible in truly de novo events. No affected relatives beyond the probands have been documented, yielding zero additional segregating cases.

Variant spectrum is dominated by glycine substitutions disrupting the Gly-X-Y repeat. A representative mutation is c.1774G>C (p.Gly592Arg) which substitutes glycine within the helix and is sufficient to predict the lethal phenotype ([PMID:1284475]).

Functional studies demonstrate that glycine substitutions result in local triple-helix unfolding, overmodification of collagen chains, reduced thermal stability and impaired procollagen secretion in patient fibroblasts. Biochemical assays show decreased melting temperature and production of disulfide-bonded collagen fragments, confirming helix destabilization ([PMID:1284475]).

Integration of genetic and functional data supports a Moderate clinical validity classification. COL1A2 glycine substitutions act via a dominant-negative mechanism, and prenatal DNA analysis combined with imaging enables early diagnosis. Key take-home: Heterozygous glycine substitutions in COL1A2 reliably predict lethal OI type II and guide prenatal counseling.

References

• Prenatal diagnosis • 1993 • First-trimester prenatal diagnosis of osteogenesis imperfecta type II by DNA analysis and sonography PMID:8415424
• Congenital anomalies • 2012 • Prenatal diagnosis of osteogenesis imperfecta type II by three-dimensional computed tomography: the current state of fetal computed tomography PMID:23181495
• Human mutation • 1992 • Lethal perinatal osteogenesis imperfecta due to a type I collagen alpha 2(I) Gly to Arg substitution detected by chemical cleavage of an mRNA:cDNA sequence mismatch PMID:1284475

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