COL2A1 – Stickler syndrome type 1

COL2A1 encodes the pro α1(II) chain of type II collagen, a major cartilage extracellular matrix component. Heterozygous COL2A1 variants cause Stickler syndrome type 1, an autosomal dominant arthro-ophthalmopathy characterized by ocular anomalies, midface retrusion, cleft palate and sensorineural hearing loss. These features overlap with other type II collagenopathies but are defined by abnormal vitreous and a high risk of rhegmatogenous retinal detachment.

Genetic evidence supports a definitive gene–disease association. Over 188 probands carrying heterozygous COL2A1 loss-of-function and dominant-negative variants have been reported, including nonsense, frameshift, splice site, missense and deep-intronic changes, consistent with haploinsufficiency and structural collagen defects (PMID:20179744). One recurrent missense allele, c.2710C>T (p.Arg904Cys), was documented in a South African family with four affected members exhibiting Stubby digits, myopia and conductive hearing loss (PMID:9800905).

Segregation data include at least 19 additional affected relatives with cosegregating COL2A1 variants across multiple families (PMID:32427345), plus a mother–daughter mosaic for a 28 bp deletion spanning exon 12, accounting for a Stickler-like phenotype in the mother and classic Kniest dysplasia features in her daughter (PMID:7981752).

Functional studies reveal that COL2A1 premature termination codons undergo nonsense-mediated mRNA decay, resulting in haploinsufficiency, as shown by cycloheximide-protected RT-PCR and in vitro protein truncation tests (PMID:10706362). Animal models recapitulate type IIA/IIB splicing defects and C-propeptide mutations: an ENU-induced p.Asp1469Ala mouse exhibits platyspondylic lethal skeletal dysplasia, ER stress and chondrocyte apoptosis, mirroring human PLSD-T (PMID:21538020).

No studies have refuted the COL2A1–Stickler syndrome type 1 link. Alternative phenotypes arise with exon 2-only mutations (ocular variant) but represent allelic heterogeneity rather than conflict.

Collectively, robust genetic and experimental evidence confirms COL2A1 as the causative gene for autosomal dominant Stickler syndrome type 1. Genetic testing enables early ophthalmological surveillance and intervention to prevent vision loss.

References

• Nature Genetics • 1993 • Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. PMID:7981752
• American Journal of Medical Genetics • 1998 • Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene. PMID:9800905
• European Journal of Human Genetics • 2010 • Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. PMID:20179744
• Annals of Human Genetics • 2020 • Expanding the phenotype spectrum associated with pathogenic variants in the COL2A1 and COL11A1 genes. PMID:32427345
• American Journal of Medical Genetics • 2000 • Molecular diagnosis of Stickler syndrome: a COL2A1 stop codon mutation screening strategy that is not compromised by mutant mRNA instability. PMID:10706362
• Mammalian Genome • 2011 • ENU-induced missense mutation in the C-propeptide coding region of Col2a1 creates a mouse model of platyspondylic lethal skeletal dysplasia, Torrance type. PMID:21538020

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