OPN1MW – Blue Cone Monochromacy

OPN1MW encodes the middle-wavelength-sensitive cone opsin on Xq28. Pathogenic variants disrupt L- and M-cone function, leading to blue cone monochromacy (BCM), an X-linked recessive disorder characterized by absent red and green cone sensitivities and severe color vision deficiency (MONDO:0010563).

Genetic analyses across five independent cohorts have identified two principal classes of pathogenic alleles in OPN1MW: deletions of the locus control region (LCR) upstream of the OPN1LW/OPN1MW cluster and inactivating point mutations within isolated genes. Thirty-four unrelated affected males have been reported: one with an exon 4 deletion (PMID:8792812), two families with precise LCR deletions (PMID:27274860), seven patients from four families harboring an exon 3 splicing haplotype (PMID:35743313), and 23 male patients with the recurrent Cys203Arg missense variant (PMID:35769953; PMID:36301530). Segregation in sibships and mothers as carriers confirms X-linked recessive inheritance.

Variant spectrum includes LCR deletions, intragenic exon 4 deletion, and missense mutations. The most frequent pathogenic allele is c.607T>C (p.Cys203Arg), observed in 15 of 23 imaged patients by adaptive optics and in cellular screens (PMID:35769953; PMID:36301530). The exon 3 haplotype (G-C-G-A-T-T-G-G) induces a strong but incomplete splicing defect with 3–5% residual transcript, correlating with a milder BCM or Bornholm eye disease–like phenotype (PMID:35743313).

Functional studies demonstrate a clear loss-of-function mechanism. Minigene assays in HEK293 and WERI-Rb1 cells confirm aberrant splicing for the exon 3 haplotype. A mouse knock-in of the equivalent C198R mutation recapitulates shortened or absent cone outer segments and loss of function; targeted gene augmentation restores cone structure and phototransduction protein expression in early-treated animals (PMID:38060327).

No studies to date have refuted the OPN1MW–BCM association. The cumulative evidence—robust segregation, recurrent variants in multiple families, concordant in vitro splicing defects, in vivo structural and functional rescue in an animal model—meets criteria for a Definitive gene–disease relationship.

Key Take-home: OPN1MW variants cause X-linked recessive BCM via haploinsufficiency and misfolding; genetic testing and emerging gene therapy approaches provide clear diagnostic and therapeutic pathways.

References

• Human genetics • 1996 • A new mechanism in blue cone monochromatism. PMID:8792812
• Human genome variation • 2016 • Novel OPN1LW/OPN1MW deletion mutations in 2 Japanese families with blue cone monochromacy. PMID:27274860
• International journal of molecular sciences • 2022 • Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction. PMID:35743313
• Journal of pediatric genetics • 2022 • Blue Cone Monochromatism: A Case Report with Opsoclonus and Light Exposure. PMID:35769953
• Investigative ophthalmology & visual science • 2022 • Foveal Cone Structure in Patients With Blue Cone Monochromacy. PMID:36301530
• JCI insight • 2024 • Structural and functional rescue of cones carrying the most common cone opsin C203R missense mutation. PMID:38060327

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