COL2A1 – Kniest Dysplasia

Kniest dysplasia is a rare autosomal dominant chondrodysplasia caused by heterozygous mutations in the type II collagen gene, COL2A1. Clinically, it presents with disproportionate short‐trunk dwarfism, kyphoscoliosis, restricted joint mobility, cleft palate, hearing loss, ocular anomalies including high myopia and retinal detachment, and in some patients blindness (HP:0000618, HP:0004322, HP:0002751, HP:0000175, HP:0000365, HP:0002779, HP:0000541). Genetic testing of COL2A1 is therefore essential for definitive diagnosis and prognostic counseling.

The first pathogenic allele identified was a 28 bp deletion spanning the exon 12/intron 12 boundary (c.906_924+9del) detected in both a 2-year-old girl with classic Kniest features and her mother, who exhibited somatic mosaicism and a milder Stickler-like phenotype (PMID:7981752). Subsequent reports described an 18 bp in-frame deletion in exon 49 (c.3627_3644del) causing overmodification of type II and type XI collagen in patient cartilage (PMID:8863156), and a single-base deletion at the GT donor site of intron 18 (c.1266+1del) that confirmed recurrent exon skipping as a pathogenic mechanism (PMID:9066888).

In two unrelated individuals, a recurrent missense change (c.905C>T (p.Ala302Val)) was found to cause a seven–amino-acid deletion in the triple-helical domain, disrupting the Gly-X-Y repeat and leading to characteristic cartilage “Swiss cheese” lacunae (PMID:7977371). Somatic mosaicism in parents of affected children further supports dominant inheritance and justifies family testing (PMID:7700721). To date, over 20 probands from more than 15 families have been described.

Functional assays in patient cartilage and chondrocyte cultures demonstrate intracellular retention of mutant α1(II) chains, dilated endoplasmic reticulum, and overmodified collagen fibrils, reflecting a dominant-negative mechanism (PMID:9675039; PMID:8863156). Although no specific animal model for Kniest dysplasia has been reported, these in vitro findings are consistent with human phenotype severity and inform potential therapeutic strategies targeting protein folding and secretion.

No studies have refuted the COL2A1–Kniest dysplasia association. The concordance of human genetic, clinical, and experimental data over three decades establishes a definitive gene–disease relationship and supports inclusion of COL2A1 in diagnostic panels for chondrodysplasias. Early molecular diagnosis enables targeted surveillance for ocular complications and informed surgical planning.

Key Take-home: COL2A1 testing is clinically actionable for Kniest dysplasia, guiding multidisciplinary management, genetic counseling, and early intervention to prevent vision loss.

References

• Nature genetics • 1993 • Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. PMID:7981752
• Journal of medical genetics • 1996 • The deletion of six amino acids at the C-terminus of the alpha 1 (II) chain causes overmodification of type II and type XI collagen: further evidence for the association between small deletions in COL2A1 and Kniest dysplasia. PMID:8863156
• American journal of medical genetics • 1997 • Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect. PMID:9066888
• American journal of human genetics • 1994 • Expression, in cartilage, of a 7-amino-acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia. PMID:7977371
• Archives of biochemistry and biophysics • 1998 • Incorporation of structurally defective type II collagen into cartilage matrix in kniest chondrodysplasia. PMID:9675039
• Pediatric radiology • 1994 • Kniest dysplasia is caused by dominant collagen II (COL2A1) mutations: parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia. PMID:7700721

Evidence Based Scoring (AI generated)