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Collagen type I, the primary structural protein in bone, is a heterotrimer composed of two pro-alpha1(I) and one pro-alpha2(I) chains, encoded by COL1A1 and COL1A2, respectively. Heterozygous glycine substitutions in the Gly-X-Y repeats of the COL1A2 triple helix underlie autosomal dominant osteogenesis imperfecta (OI) type IV, a non-lethal form characterized by moderate bone fragility without blue sclerae (Disease Name).
Three unrelated families harboring glycine substitution variants in COL1A2 have been described as causative for OI type IV. A fetal case and multiple affected relatives from one pedigree carried c.2197G>T (p.Gly733Cys) segregating with OI type IV across five members (PMID:22795107). In a second family, the missense change c.2746G>A (p.Gly916Arg) was identified in the proband and affected kin (PMID:25835785). A Thai father–daughter pair with OI type IV and dentinogenesis imperfecta shared c.1451G>A (p.Gly484Glu) (PMID:29636545).
Autosomal dominant inheritance is supported by segregation of the heterozygous variants in multiple affected individuals: at least five additional relatives beyond index cases in one kindred (PMID:22795107)). Glycine substitutions disrupt the tight triple-helix packing, consistent across all three families.
The variant spectrum in OI type IV is dominated by glycine substitutions within the triple-helical domain, with missense changes (Gly→Cys or Gly→Arg) impairing helix stability. No recurrent or population-specific founder alleles have been reported to date in COL1A2 for type IV OI; carrier frequency data are not established.
Experimental assays demonstrate that glycine substitutions in pro-alpha2(I) collagen reduce thermal stability of the helix, increase protease sensitivity, and lead to intracellular collagen retention and overmodification, concordant with the OI phenotype. Biochemical analysis of mutant fibroblast collagen corroborates triple-helix destabilization.
Integration of genetic segregation and biochemical concordance supports a Moderate clinical validity classification for COL1A2 in OI type IV. Further studies could expand variant spectrum and quantitative genotype–phenotype correlations. Key take-home: COL1A2 glycine substitutions reliably indicate autosomal dominant OI type IV and inform diagnostic genetic testing and counseling.
Gene–Disease AssociationModerateThree unrelated families with pathogenic glycine substitutions in COL1A2, segregation in a multi-generational pedigree and concordant collagen assays Genetic EvidenceModerateGlycine substitution variants in three families (total probands = 3) with AD inheritance and segregation evidence Functional EvidenceModerateProtease and thermal stability assays show helix destabilization; overmodified collagen retention seen in patient fibroblasts |