COL2A1 – Spondyloperipheral Dysplasia

Autosomal dominant spondyloperipheral dysplasia (SPD; MONDO:0010078) is a rare type II collagenopathy characterized by short stature, platyspondyly, and brachydactyly type E. Clinical variability ranges from lethal perinatal forms to milder non-lethal presentations within the SPD–Torrance spectrum. Mutations cluster in the C-propeptide region of COL2A1, defining SPD as a distinct entity within the type II collagenopathies.

Genetic evidence supports a dominant-negative mechanism. Five unrelated families with eight probands ([PMID:8723097], [PMID:21356074], [PMID:22495950], [PMID:15316962], [PMID:23545312]) harbor heterozygous truncating or in-frame C-propeptide variants. Segregation in mother–child and mosaic mother–fetus pairs confirms germline transmission and recurrent de novo occurrence ([PMID:22495950]).

The variant spectrum includes frameshift duplications (c.4287_4291dup (p.Tyr1431SerfsTer6)), in-frame deletions (c.4458_4460del (p.Phe1486del)), and nonsense changes (c.4314C>A (p.Cys1438Ter), c.4293C>A (p.Tyr1431Ter)) all predicted to escape nonsense-mediated decay and disrupt C-propeptide folding.

Functional studies demonstrate that mutant procollagen chains accumulate in the endoplasmic reticulum, alter chondrocyte morphology and collagen fibril architecture ([PMID:8723097]), and induce ER stress–mediated apoptosis in growth plate chondrocytes in a mouse C-propeptide missense model (p.Tyr1391Ser) ([PMID:26545783]).

Integration of genetic and experimental data defines SPD as a dominantly inherited collagenopathy driven by toxic accumulation of C-propeptide-truncated chains, distinguishing it from null haploinsufficiency and triple-helical domain disorders. No conflicting evidence has been reported.

Key Take‐home: C-propeptide variants in COL2A1 should be sought in individuals with platyspondyly and brachydactyly type E to confirm SPD diagnosis, inform recurrence risk, and guide management.

References

• American journal of medical genetics • 1996 • A specific collagen type II gene (COL2A1) mutation presenting as spondyloperipheral dysplasia. PMID:8723097
• Orphanet journal of rare diseases • 2011 • Prenatal manifestation and management of a mother and child affected by spondyloperipheral dysplasia with a C-propeptide mutation in COL2A1: case report. PMID:21356074
• American journal of medical genetics. Part A • 2012 • Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dysplasia torrance type in mother and fetus with the same COL2A1 mutation. PMID:22495950
• American journal of medical genetics. Part A • 2004 • Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1. PMID:15316962
• Gene • 2013 • Identification of one novel mutation in the C-propeptide of COL2A1 in a Chinese family with spondyloperipheral dysplasia. PMID:23545312
• Biochemical and biophysical research communications • 2015 • Endoplasmic reticulum stress-mediated apoptosis contributes to a skeletal dysplasia resembling platyspondylic lethal skeletal dysplasia, Torrance type, in a novel Col2a1 mutant mouse line. PMID:26545783

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