Bornholm eye disease (BED)
1,2 has been distinguished from other X-linked cone dysfunction syndromes by its association with red-green color vision deficiency, myopia, and astigmatism, in addition to other general cone dysfunction characteristics.
3 The disease in the original Danish family and in a Minnesota family with a similar phenotype was mapped to Xq28 (the locus of
MYP1),
4 which encompasses the long (L) and middle (M) wavelength sensitive opsin genes
OPN1LW and
OPN1MW, respectively. Ultimately, the same underlying mutation in the cone opsin genes, designated LVAVA, was found in both families.
5,6 This “interchange-mutation” is associated with a combination of amino acids designated by the single letter code for the amino acids specified by exon 3 codons 153, 171, 174, 178, and 180, respectively, where L is leucine, V is valine, and A is alanine.
7 Although both of the original
MYP1 families had color vision deficiencies, which was a defining feature of BED, affected members of four additional families with X-linked high myopia of Chinese ancestry,
8–10 also mapped to
MYP1, were later found to have normal color vision. The original (
MYP1) families coincidentally had separate gene rearrangements responsible for their color vision deficiency, while the LVAVA mutation was responsible for the myopia and other cone dysfunction symptoms. In addition to altering the amino acid sequence, the underlying nucleotide combination introduces an exon 3 splicing defect that greatly reduces production of normal opsin. Cones expressing the mutant opsin appear to function well enough to support normal color vision in younger eyes but degenerate over time.
11 The malfunctioning cones lead to high myopia and cone degenerative symptoms in individuals with a submosaic of LVAVA-expressing cones, along with a submosaic of cones expressing normal pigment. The same mutation produces progressive cone dystrophy with significant vision loss by midlife in individuals who express LVAVA opsin in all L/M cones.
11