COL1A1 – osteogenesis imperfecta type I

COL1A1 is robustly associated with osteogenesis imperfecta type I, an autosomal dominant disorder characterized by bone fragility, blue sclerae, dentinogenesis imperfecta, and conductive hearing loss. Patients produce approximately half the normal amount of proα1(I) collagen chains due to heterozygous null or splice‐site variants that trigger nonsense‐mediated mRNA decay and prevent synthesis of mutant protein (PMID:8408653).

Extensive genetic studies across unrelated families have identified over 150 distinct COL1A1 null alleles—including nonsense, frameshift, splice‐site, and whole‐gene deletions—in more than 200 probands, with segregation of pathogenic variants in at least 12 additional affected relatives (PMID:7942841; PMID:35855543). Case reports and series document recurrent splice donor mutations (e.g., c.1821+1G>A), premature termination codons in the triple helix, and frame‐shift deletions leading to haploinsufficiency (PMID:27044453).

The variant spectrum includes: 1 intronic splice‐site mutation (c.1821+1G>A), multiple nonsense variants (e.g., p.Gln105Ter), frameshifts (p.Gly356ProfsTer7), and whole‐gene deletions detected by array CGH. No founder mutations predominate; instead, private null alleles arise across diverse populations, consistent with a loss‐of‐function mechanism.

Functional assays demonstrate that splice‐site and nonsense variants yield unstable nuclear transcripts retaining intronic sequences, marked reduction of steady‐state mRNA, and abrogated collagen secretion in patient fibroblasts (PMID:8808594). Rescue experiments are not required for OI‐I phenotypes, as the mild clinical presentation reflects absence of dominant‐negative protein.

Gene‐targeting in mice deleting COL1A1 intronic cis‐elements confirms that disruption of normal splicing reduces transcript levels in a tissue‐specific manner, yet retains inducible expression under profibrotic stimuli, mirroring human haploinsufficiency (PMID:9584177). These concordant in vitro and in vivo data underpin a pathogenic mechanism of COL1A1 haploinsufficiency.

Integration of genetic and functional evidence establishes a Definitive association between COL1A1 and OI type I. Clinical genetic testing for COL1A1 null and splice variants is indicated for diagnosis, carrier screening, and prenatal decision‐making, enabling precise counseling and management of fracture risk and hearing interventions.

References

• The Journal of clinical investigation • 1993 • Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta PMID:8408653
• American journal of human genetics • 1994 • Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen PMID:7942841
• Molecular genetics & genomic medicine • 2022 • Analysis of the clinical and genetic characteristics of a Chinese family with osteogenesis imperfecta type I PMID:35855543
• Acta oto-laryngologica • 2016 • Identification of two recurrent mutations of COL1A1 gene in Chinese Van der Hoeve syndrome patients PMID:27044453
• American journal of human genetics • 1996 • Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains PMID:8808594
• Molecular and cellular biology • 1998 • A gene-targeting approach identifies a function for the first intron in expression of the alpha1(I) collagen gene PMID:9584177

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