COL2A1 – Achondrogenesis Type II

Achondrogenesis type II (ACG2; MONDO:0008702) is a perinatal‐lethal skeletal dysplasia characterized by extreme micromelia, thoracic hypoplasia, generalized edema, hydrops fetalis, and gelatinous cartilage. This disorder arises from autosomal dominant mutations in COL2A1 (HGNC:2200), which encodes the α1(II) chain of type II collagen, the primary collagen in cartilage.

Clinical Validity

The association between COL2A1 and ACG2 is categorized as Strong based on at least 9 unrelated probands harboring de novo glycine substitutions disrupting the Gly-X-Y repeat essential for triple-helix stability and consistent biochemical findings. Recurrent mutations have been observed in two families due to germline mosaicism, reinforcing pathogenicity ([PMID:7829510]; [PMID:15054848]; [PMID:20583175]).

Genetic Evidence

Inheritance is autosomal dominant with primarily de novo events. Across 9 probands, glycine substitutions cluster within the triple‐helical domain (e.g., c.2905G>A (p.Gly969Ser)), each absent from parental germlines ([PMID:7829510]; [PMID:25823796]; [PMID:36376277]). Two families show recurrence in sibs without parental transmission, indicating germline mosaicism and supporting a genetic mechanism of dominant negative effect.

Functional / Experimental Evidence

Functional assays demonstrate that glycine substitutions abolish secretion of stable type II collagen, resulting in its intracellular retention and proteolysis. Cartilage from affected fetuses lacks type II collagen and is replaced by type I and III collagens, yielding gelatinous matrix and aberrant chondrocyte maturation ([PMID:7829510]). In vitro studies confirm delayed secretion and post‐translational overmodification of mutated collagen chains and decreased thermal stability, consistent with dominant‐negative disruption of fibrillogenesis ([PMID:7741714]; [PMID:10797431]).

Conflicting Evidence

No studies to date report benign glycine substitutions at analogous positions without cartilage phenotype, and no alternative genetic etiologies have been implicated in true ACG2 cases, minimizing conflicting evidence.

Integration & Clinical Utility

COL2A1 glycine substitutions are consistently linked to lethal ACG2 through a dominant‐negative mechanism, with clear histopathological and biochemical concordance. Molecular diagnosis via sequencing of COL2A1 exon 41 and adjacent triple‐helix–encoding exons allows definitive prenatal and postnatal diagnosis, informs recurrence risk (including mosaicism), and guides genetic counseling. Early detection supports decision-making for perinatal management and family planning.

Key Take-home: COL2A1 glycine‐substitution mutations cause autosomal dominant achondrogenesis type II via dominant‐negative disruption of type II collagen triple‐helix formation, enabling definitive genetic diagnosis and counseling.

References

• The Journal of Biological Chemistry • 1995 • A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage. PMID:7829510
• American Journal of Medical Genetics Part A • 2004 • Recurrence of achondrogenesis type II within the same family: evidence for germline mosaicism. PMID:15054848
• American Journal of Medical Genetics Part A • 2010 • Recurrence of achondrogenesis type 2 in sibs: Additional evidence for germline mosaicism. PMID:20583175
• Cytogenetic and Genome Research • 2015 • Co-Occurence of Reciprocal Translocation and COL2A1 Mutation in a Fetus with Severe Skeletal Dysplasia: Implications for Genetic Counseling. PMID:25823796
• Balkan Journal of Medical Genetics • 2019 • Achondrogenesis Type 2 in a Newborn with a Novel Mutation on the COL2A1 Gene. PMID:31523626
• Human Genome Variation • 2022 • Novel missense COL2A1 variant in a fetus with achondrogenesis type II. PMID:36376277
• American Journal of Medical Genetics • 2000 • Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. PMID:10797431

Evidence Based Scoring (AI generated)