VCAN – Wagner syndrome

Versican, encoded by VCAN (HGNC:2464), is a large extracellular matrix chondroitin sulfate proteoglycan essential for vitreous gel integrity. Wagner syndrome (MONDO:0007740) is a rare, autosomal dominant vitreoretinopathy characterized by an optically empty vitreous with avascular veils, progressive chorioretinal atrophy, cataract, and predisposition to retinal detachment (VCAN; Wagner syndrome).

Genetic evidence derives from multiple three-generation pedigrees demonstrating cosegregation of heterozygous splice‐site mutations and exon 8 deletions in VCAN with disease. A Japanese family showed a c.4004-2A>G splice acceptor variant segregating in all affected members (PMID:16043844). A Portuguese kindred exhibited a heterozygous intron 7 mutation (c.4004->A) across 28 affected relatives (PMID:29071374). Numerous additional families harbor canonical splice‐site changes (e.g., c.9265+1G>C) and multi-kilobase deletions targeting exon 8, collectively accounting for >100 probands worldwide (PMID:22739342).

Variants cluster at exon–intron boundaries of exon 8, supporting a mutational hot spot. Spectrum includes splice acceptor (c.4004-2A>G), donor (c.9265+1G>C), small indels, and multi-exon deletions leading to exon 8 skipping. Recurrent c.9265+1G>C has been reported in independent ethnic groups, underscoring diagnostic relevance.

Functional assays confirm pathogenicity: RT-PCR and qRT-PCR from patient lymphoblasts and fibroblasts show aberrant splicing with increased transcripts lacking exons 7/8, altering versican isoform balance (PMID:22739342). Proteolysis studies demonstrate loss of an MMP cleavage site due to c.4004-2A>G, impacting vitreous remodeling (PMID:30657523). Additional cellular models indicate that versican dysregulation perturbs vitreous structure and predisposes to tractional forces.

No conflicting evidence disputing the VCAN–Wagner link has emerged. Phenotypic overlap with Stickler syndrome is resolved by absence of COL2A1 variants in VCAN-mutated families, reinforcing specificity.

In summary, autosomal dominant VCAN splice and structural variants cause haploinsufficiency of exon 8–containing transcripts, leading to classic Wagner syndrome. Genetic testing of VCAN exon 8 and surrounding splice sites is critical for accurate diagnosis, counseling, and prophylactic management to mitigate retinal detachment risk.

References

• Investigative ophthalmology & visual science • 2005 • Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome. PMID:16043844
• Graefe's archive for clinical and experimental ophthalmology • 2018 • WAGNER syndrome: anatomic, functional and genetic characterization of a Portuguese family. PMID:29071374
• European Journal of Human Genetics • 2013 • Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome. PMID:22739342
• Investigative Ophthalmology & Visual Science • 2019 • VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site. PMID:30657523
• Molecular Genetics & Genomic Medicine • 2023 • A novel splicing variant of VCAN identified in a Chinese family initially diagnosed with familial exudative vitreoretinopathy. PMID:36333947

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