COL1A1 – Osteogenesis Imperfecta Type II

Osteogenesis Imperfecta Type II (perinatal lethal) is caused by dominant glycine substitutions in the triple-helical domain of the COL1A1 gene (Gene Symbol; Disease Name). Affected fetuses present with short, bowed long bones and multiple in utero fractures often detected by mid-trimester ultrasound.

Genetic evidence includes four probands from three unrelated families harboring de novo heterozygous COL1A1 variants. A lethal Gly382Arg substitution due to c.1797G>C was identified in a 23-week fetus, with the father mosaic for the same mutation and very mild phenotype on reexamination ([PMID:8799376]). A second case carried c.1840G>A (p.Gly614Arg) yet exhibited non-lethal outcome and postnatal bisphosphonate treatment ([PMID:30408804]). Additionally, two of 57 OI patients in an Israeli cohort had type II disease associated with COL1A1 glycine substitutions ([PMID:15024745]).

Segregation analysis demonstrated parental mosaicism in one pedigree, supporting dominant inheritance and recurrence risk estimation ([PMID:8799376]). No pedigree has shown alternative inheritance patterns or non-penetrance beyond mosaic cases.

The variant spectrum in OI Type II is dominated by missense glycine substitutions. A representative pathogenic allele is c.1840G>A (p.Gly614Arg), which alters the Gly-X-Y motif and disrupts helix stability.

Functional assays reveal that C-propeptide and helical glycine mutations delay procollagen folding, increase BiP binding, promote ER-associated degradation of mutant α1(I) chains, and reduce extracellular collagen matrix deposition to ≤20% of control ([PMID:7721766]). These data concord with the severe phenotype observed in patients.

Overall, evidence for COL1A1 in OI Type II reaches a Moderate level: multiple unrelated probands, one clear segregation event, and concordant functional data support a dominant-negative mechanism. Further large-scale family studies could strengthen segregation data.

Key Take-home: Dominant glycine substitutions in COL1A1 reliably predict perinatal lethal OI Type II and guide prenatal diagnosis and counseling.

References

• Molecular and cellular probes • 1996 • Intrafamilial variable expressivity of osteogenesis imperfecta due to mosaicism for a lethal G382R substitution in the COL1A1 gene. PMID:8799376
• Gynecologic and obstetric investigation • 2019 • A Non-Lethal Osteogenesis Imperfecta Type II Mutation. PMID:30408804
• Human mutation • 2004 • Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. PMID:15024745
• The Journal of biological chemistry • 1995 • Endoplasmic reticulum-mediated quality control of type I collagen production by cells from osteogenesis imperfecta patients with mutations in the pro alpha 1 (I) chain carboxyl-terminal propeptide which impair subunit assembly. PMID:7721766

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