COL2A1 – Hypochondrogenesis

COL2A1 encodes the α1(II) chain of type II collagen, the principal fibrillar collagen in cartilage. Germline missense mutations substituting the obligate glycine in the Gly-X-Y repeat destabilize the triple helix and underlie a spectrum of type II collagenopathies ranging from Stickler syndrome to perinatal lethal hypochondrogenesis.

Three unrelated probands with lethal hypochondrogenesis harbor heterozygous glycine substitutions in the C-terminal region of the triple-helical domain: c.2411G>C (p.Gly804Ala) in exon 35 detected in a 38-week fetus (PMID:8175802), c.3337G>T (p.Gly1113Cys) in a neonate (PMID:8723098), and c.3013G>A (p.Gly1005Ser) in a separate case (PMID:7741714).

All cases represent de novo heterozygous events consistent with autosomal dominant inheritance and show no evidence of multigenerational segregation, underscoring a dominant-negative mechanism.

Functional analyses of patient cartilage and cultured chondrocytes demonstrate post-translational overmodification of collagen II CNBr peptides, failure of type II collagen secretion, incorporation of type I and III collagens into the matrix, reduced extracellular matrix density, and disorganized growth plate architecture (PMID:8175802).

Biochemical and histologic concordance across studies indicates that glycine substitutions in COL2A1 exert a dominant-negative effect, destabilize collagen II fibrils, induce endoplasmic reticulum stress, and impair endochondral ossification in hypochondrogenesis.

Although the total number of reported families is limited, consistent genotype–phenotype and functional evidence support a Limited yet clinically actionable association. Key take-home: molecular testing for COL2A1 glycine substitutions enables definitive prenatal diagnosis of hypochondrogenesis and informs perinatal management.

References

• The Journal of biological chemistry | 1994 | Mutation in the COL2A1 gene in a patient with hypochondrogenesis. Expression of mutated COL2A1 gene is accompanied by expression of genes for type I procollagen in chondrocytes. PMID:8175802
• American journal of medical genetics | 1996 | An alpha 1(II) Gly913 to Cys substitution prevents the matrix incorporation of type II collagen which is replaced with type I and III collagens in cartilage from a patient with hypochondrogenesis. PMID:8723098
• The Biochemical journal | 1995 | Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis: analysis of genotype-phenotype relationships. PMID:7741714

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