COL1A1 – Osteogenesis Imperfecta Type IV

COL1A1 encodes the pro-α1(I) chain of type I collagen, a critical structural protein in bone. Heterozygous pathogenic variants in COL1A1 underlie autosomal dominant forms of osteogenesis imperfecta (OI), including the moderate phenotype classified as OI type IV. The documented association between COL1A1 and Osteogenesis Imperfecta Type IV is supported by multiple unrelated probands, familial segregation, and concordant biochemical studies.

The clinical validity is classified as Strong based on ClinGen criteria. A cohort of 57 Israeli OI patients included 8 individuals with OI type IV carrying COL1A1 variants (PMID:15024745) and an independent family with a fetally diagnosed case (PMID:25835785). Functional assays demonstrating defective collagen folding and secretion further corroborate pathogenicity.

OI type IV exhibits autosomal dominant inheritance with variable expressivity, including bone fragility, fractures, and reduced bone density. Segregation analysis in the antenatal diagnosis family confirmed variant co-segregation in one affected relative. Across studies, at least nine probands carry COL1A1 variants, encompassing missense glycine substitutions, nonsense, frameshift, splice-site, and in-frame deletion alleles.

The variant spectrum in OI type IV includes glycine substitutions within the triple helix and null alleles. A representative pathogenic change is c.1243C>T (p.Arg415Ter), which leads to premature termination and triggers nonsense-mediated mRNA decay. Such haploinsufficiency mutations correlate with the intermediate clinical severity of type IV.

Mechanistically, mutant pro-α1(I) chains misfold, accumulate in the endoplasmic reticulum, and are inefficiently secreted, resulting in overmodified collagen and a deficient extracellular matrix (PMID:7721766). This cellular phenotype mirrors the bone matrix abnormalities observed in OI patients.

In summary, autosomal dominant COL1A1 variants cause OI type IV through haploinsufficiency and dominant-negative effects on collagen assembly. The combination of genetic and functional data meets ClinGen standards for a strong gene–disease association, enabling reliable clinical diagnosis and genetic counseling. Key Take-home: COL1A1 sequencing is essential for the diagnosis and antenatal management of OI type IV.

References

• Medical science monitor : international medical journal of experimental and clinical research • 2015 • Clinical application of antenatal genetic diagnosis of osteogenesis imperfecta type IV. PMID:25835785
• 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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