COL2A1 – Autosomal dominant rhegmatogenous retinal detachment

COL2A1 encodes the α1 chain of type II collagen, a key component of vitreous structure. Heterozygous mutations in COL2A1 have been implicated in an ocular‐only form of autosomal dominant rhegmatogenous retinal detachment ([PMID:12939326]). This phenotype is distinct from syndromic Stickler disease, presenting primarily with retinal tears or detachments without systemic features.

Inheritance is autosomal dominant, with complete cosegregation in multiple pedigrees. Linkage analysis in two large families yielded maximum LOD scores of 6.09 and 4.97, respectively, at the COL2A1 locus ([PMID:12939326]). Affected individuals in family A (n = 15) and family B (n = 12) exhibited retinal detachment or tears with minimal or absent syndromic signs ([PMID:12939326]).

Case series and molecular screening identified a truncating variant c.1957C>T (p.Arg653Ter) and a novel missense variant c.952G>A (p.Gly318Arg) in affected members. The c.1957C>T (p.Arg653Ter) change occurs in the triple helical domain and is known to destabilize collagen trimers, leading to vitreous degeneration ([PMID:12939326]).

Functional assessment using splicing reporter minigenes for DRRD‐associated mutations (Gly118Arg, Arg453Ter, Leu467Phe) in cultured cells demonstrated no aberrant exon 2 splicing or cryptic splice‐site usage ([PMID:15671297]). These data suggest that altered collagen fibril assembly rather than mRNA missplicing underlies the ocular‐only phenotype.

No conflicting evidence has been reported against the role of COL2A1 truncating or glycine‐substitution mutations in DRRD. The molecular and segregation data together support a direct pathogenic mechanism via collagen structural perturbation.

Key Take-home: COL2A1 mutations result in autosomal dominant rhegmatogenous retinal detachment through a collagen structural mechanism, informing genetic testing and early ophthalmologic surveillance in at-risk individuals.

References

• Investigative Ophthalmology & Visual Science • 2003 • Autosomal dominant rhegmatogenous retinal detachment associated with an Arg453Ter mutation in the COL2A1 gene. PMID:12939326
• Investigative Ophthalmology & Visual Science • 2005 • A novel mutation of COL2A1 resulting in dominantly inherited rhegmatogenous retinal detachment. PMID:15671297

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