OPN1LW – Blue Cone Monochromacy

Blue Cone Monochromacy is an X-linked recessive cone dysfunction disorder characterized by absence of long- and middle-wavelength cone sensitivities, severe color vision deficits, reduced visual acuity, and high myopia. Affected males present in early childhood with lifelong visual impairment and nystagmus, while female carriers may show subclinical retinal changes.

Early genetic studies identified a pedigree with gene conversion transferring the Cys203Arg missense mutation (c.607T>C (p.Cys203Arg)) from OPN1MW into OPN1LW, abolishing opsin function and causing BCM (PMID:8666378). Subsequent case reports described isolated intragenic deletions of exon 4 in an OPN1LW gene (PMID:8792812) and recurrent Cys203Arg variants in sporadic BCM cases (PMID:35769953). Two Japanese families with upstream locus control region deletions and fifteen additional males with c.607T>C (p.Cys203Arg) plus eight with LCR deletions confirmed segregation of OPN1LW variants in at least 23 probands (PMID:27274860; PMID:36301530).

The variant spectrum in BCM includes the recurrent missense mutation c.607T>C (p.Cys203Arg), gene conversion events creating hybrid opsin genes, intragenic exon 4 deletions, and large LCR deletions upstream of the opsin cluster. All classes result in loss of functional long-wavelength opsin expression in cone photoreceptors.

Functional assays using minigene constructs for exon 3 and exon 4 haplotypes demonstrate severe splicing defects with <5% residual correctly spliced transcripts, providing mechanistic evidence of OPN1LW loss-of-function. High-resolution adaptive optics imaging of BCM patients corroborates a marked reduction in waveguiding L/M cones, confirming disrupted cone structure and function in vivo (PMID:35743313).

No significant conflicting reports have been published to dispute the causal role of OPN1LW variants in BCM. The consistency of X-linked segregation across multiple pedigrees and concordant functional and clinical data support a definitive gene–disease relationship.

Key Take-home: OPN1LW molecular testing is essential for confirming blue cone monochromacy, guiding genetic counseling, carrier detection, and informing eligibility for emerging cone-targeted therapies.

References

• Genomics • 1995 • Gene conversion between red and defective green opsin gene in blue cone monochromacy. PMID:8666378
• Human genetics • 1996 • A new mechanism in blue cone monochromatism. PMID:8792812
• Journal of pediatric genetics • 2022 • Blue Cone Monochromatism: A Case Report with Opsoclonus and Light Exposure. PMID:35769953
• Human genome variation • 2016 • Novel OPN1LW/OPN1MW deletion mutations in 2 Japanese families with blue cone monochromacy. PMID:27274860
• Investigative ophthalmology & visual science • 2022 • Foveal Cone Structure in Patients With Blue Cone Monochromacy. PMID:36301530
• International journal of molecular sciences • 2022 • Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction. PMID:35743313

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