Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction

Int J Mol Sci. 2022 Jun 20;23(12):6868. doi: 10.3390/ijms23126868.


Certain combinations of common variants in exon 3 of OPN1LW and OPN1MW, the genes encoding the apo-protein of the long- and middle-wavelength sensitive cone photoreceptor visual pigments in humans, induce splicing defects and have been associated with dyschromatopsia and cone dysfunction syndromes. Here we report the identification of a novel exon 3 haplotype, G-C-G-A-T-T-G-G (referring to nucleotide variants at cDNA positions c.453, c.457, c.465, c.511, c.513, c.521, c.532, and c.538) deduced to encode a pigment with the amino acid residues L-I-V-V-A at positions p.153, p.171, p.174, p.178, and p.180, in OPN1LW or OPN1MW or both in a series of seven patients from four families with cone dysfunction. Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual correctly spliced transcripts. Minigene splicing outcomes were similar in HEK293 cells and the human retinoblastoma cell line WERI-Rb1, the latter retaining a cone photoreceptor expression profile including endogenous OPN1LW and OPN1MW gene expression. Patients carrying the novel L-I-V-V-A haplotype presented with a mild form of Blue Cone Monochromacy or Bornholm Eye Disease-like phenotype with reduced visual acuity, reduced cone electroretinography responses, red-green color vision defects, and frequently with severe myopia.

Keywords: Blue Cone Monochromacy; Bornholm Eye Disease; cone photoreceptor LWS and MWS opsin genes; exonic splicing defect; haplotype; minigene assay.

MeSH terms

  • Color Vision Defects* / genetics
  • Color Vision Defects* / metabolism
  • Exons / genetics
  • HEK293 Cells
  • Haplotypes
  • Humans
  • Retinal Cone Photoreceptor Cells / metabolism
  • Rod Opsins / genetics*
  • Rod Opsins / metabolism


  • Rod Opsins
  • long-wavelength opsin
  • middle-wavelength opsin