Genetic Disorders of Collagen and Associated Phenotypes

Collagen underpins the structural integrity of connective tissues throughout the body. Mutations in genes encoding fibrillar and non-fibrillar collagens give rise to a spectrum of hereditary disorders collectively termed collagenopathies. These include osteogenesis imperfecta, characterised by bone fragility and blue sclerae; Ehlers–Danlos syndromes, defined by skin hyperextensibility and joint hypermobility; Stickler syndromes, featuring ocular defects, hearing loss and craniofacial anomalies; and a range of chondrodysplasias such as spondyloepiphyseal dysplasia congenita, which present with disproportionate short stature and skeletal deformities. Pathogenic variants often involve glycine substitutions in the Gly-X-Y motif of the triple helix, causing misfolding, endoplasmic reticulum stress and aberrant extracellular matrix assembly. The nature of the mutation—whether it induces haploinsufficiency or a dominant-negative effect—modulates disease severity and tissue involvement. Advances in sequencing technologies have enabled precise genotype–phenotype correlations, informing predictive diagnostics, genetic counselling and the development of targeted therapies such as molecular chaperones and gene-editing approaches. A deeper understanding of collagen biogenesis and its regulatory pathways holds promise for novel interventions to restore tissue function and mitigate complications such as early-onset arthritis, retinal detachment and cardiopulmonary insufficiency.

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Genetic Disorders of Collagen and Associated Phenotypes publication trend

The graph below shows the total number of articles in genetic disorders of collagen and associated phenotypes across all publications each year (not limited to Nature Index journals).

Technical terms

Collagenopathy: A hereditary disorder caused by mutations in collagen-encoding genes leading to connective tissue defects.

Haploinsufficiency: A pathogenic mechanism in which loss of one gene copy reduces protein below a critical threshold, causing disease.

Dominant negative: A mutation that produces an aberrant protein which interferes with the function of the normal protein from the wild-type allele.

Glycine substitution: Replacement of glycine residues in the Gly-X-Y repeat of collagen, disrupting triple-helix stability and folding.

Triple helix: The three-chain, rope-like structure formed by collagen polypeptides, essential for tensile strength in connective tissues.

References

1. Stickler Syndrome: A Review of Clinical Manifestations and the Genetics Evaluation. Journal of Personalized Medicine (2020).
2. Endoplasmic Reticulum Stress-Unfolding Protein Response-Apoptosis Cascade Causes Chondrodysplasia in a col2a1 p.Gly1170Ser Mutated Mouse Model. PLOS ONE (2014).
3. Dominant Stickler Syndrome. Genes (2022).
4. Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I. Genes (2022).
5. Autosomal Recessive Stickler Syndrome. Genes (2022).