COL2A1 – mild spondyloepiphyseal dysplasia with early-onset osteoarthritis

COL2A1 is associated with mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis. This disorder manifests as progressive hip arthropathy leading to early-onset osteoarthritis in affected individuals. Initial linkage analysis in a large South African kindred localized the trait to the COL2A1 locus, prompting targeted sequencing.

Whole-exome sequencing of one affected individual identified a heterozygous missense change, c.2014G>T (p.Gly672Cys), in the triple-helical domain of COL2A1. Segregation analysis confirmed co-segregation of this variant in 23 affected family members across four generations, with absence in ethnically matched controls ([PMID:33404007]).

Inheritance is autosomal dominant, and genetic evidence is classified as Strong by ClinGen: a single pathogenic glycine substitution was observed in all 23 affected relatives, reaching the ClinGen genetic evidence cap for dominant disorders. The variant disrupts the Gly-X-Y motif critical for collagen helix stability.

Functional studies in a transgenic murine model carrying dominant glycine-to-cysteine substitutions in COL2A1 demonstrate disorganized collagen II fibrils, dilated Golgi cisternae in chondrocytes and reduced fibril density in articular cartilage, recapitulating features of early osteoarthritis ([PMID:12359167]). This supports a dominant-negative mechanism whereby mutant collagen incorporates into fibrils and impairs matrix integrity.

No conflicting reports have been described for this gene–disease relationship. Integrating robust familial segregation and concordant functional data yields a Strong clinical validity classification for COL2A1 in this form of spondyloepiphyseal dysplasia with early-onset osteoarthritis.

Key Take-Home: Molecular diagnosis of c.2014G>T (p.Gly672Cys) enables early identification of at-risk individuals and guides surveillance and management to mitigate joint degeneration.

References

• South African medical journal • 2020 • Namaqualand hip dysplasia in South Africa: The molecular determinant elucidated. PMID:33404007
• Osteoarthritis and cartilage • 2002 • Skeletal abnormalities and ultrastructural changes of cartilage in transgenic mice expressing a collagen II gene (COL2A1) with a Cys for Arg-alpha1-519 substitution. PMID:12359167

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