COL2A1 – Czech Dysplasia (Spondyloepiphyseal Dysplasia with Metatarsal Shortening)

Czech dysplasia is a rare autosomal dominant skeletal disorder characterized by normal stature, early-onset progressive osteoarthritis, platyspondyly, and shortening of the third and fourth metatarsals. Molecular analyses across multiple populations have pinpointed a recurrent missense mutation in the COL2A1 gene underlying this phenotype. This condition must be distinguished from rheumatoid arthritis and other collagenopathies to guide appropriate management.

Genetic evidence for COL2A1 involvement is robust. Whole-exome sequencing in a Chinese pedigree identified the heterozygous COL2A1 c.823C>T (p.Arg275Cys) in the proband and multiple affected relatives ((PMID:38020103)). Independent reports confirmed the same variant in three Japanese family members ((PMID:19764028)) and in 12 Brazilian individuals presenting with a Czech dysplasia–like phenotype, half of whom met rheumatoid arthritis criteria ((PMID:37489771)). A targeted study of the original European families found c.823C>T in two of three index patients and three additional unrelated individuals ((PMID:17726487)). In total, 16 probands across six unrelated pedigrees carry this recurrent missense change.

All affected individuals harbor a heterozygous missense substitution in exon 13 of COL2A1: c.823C>T (p.Arg275Cys). This glycine-adjacent arginine-to-cysteine change disrupts the collagen II triple helix, leading to a specific, non-lethal type II collagenopathy. The variant has arisen independently in multiple populations, consistent with a founder or hypermutable hotspot effect.

Segregation analysis demonstrates co-segregation of the variant with disease in at least eight additional affected relatives across Chinese, Japanese, and European kindreds. No other pathogenic COL2A1 alleles were identified in these families, and the variant is absent from population databases, supporting its specificity for Czech dysplasia.

Functional studies of type II collagen mutants show that p.Arg275Cys retains triple-helical stability and does not elicit endoplasmic reticulum stress or unfolded protein response in chondrocytes, unlike lethal C-propeptide mutants, aligning with the moderate clinical severity of Czech dysplasia ((PMID:18383211)). This mechanism is compatible with a dominant-negative effect limited to cartilage.

Key diagnostic take-home: Sequencing of COL2A1 exon 13 for c.823C>T (p.Arg275Cys) should be considered in patients with platyspondyly and metatarsal shortening to distinguish Czech dysplasia from rheumatoid arthritis or other type II collagenopathies.

References

• Frontiers in medicine • 2023 • Case report: Whole exome sequencing and genome-wide methylation profiling of Czech dysplasia in a Chinese pedigree. PMID:38020103
• American journal of medical genetics. Part A • 2009 • Czech dysplasia occurring in a Japanese family. PMID:19764028
• Modern rheumatology • 2024 • Czech dysplasia mimicking rheumatoid arthritis: Case series and literature review. PMID:37489771
• European journal of human genetics : EJHG • 2007 • Czech dysplasia metatarsal type: another type II collagen disorder. PMID:17726487
• Human mutation • 2008 • Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis. PMID:18383211

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