Cone Mosaic Disruption Caused by L/M Opsin Mutations in Bornholm Eye Disease

A Possible Explanation for Variable Phenotypes in Individuals With the Same Genotype Patient Characteristics Bornholm eye disease (BED) is characterized by dichromacy and cone dysfunction and was mapped to Xq28 in 1990 by Schwartz et al.1 Subsequent studies have not identified mutations within the L/M gene array believed to account for both the color vision defect and cone dysfunction. We have previously found that a specific combination of polymorphisms (LIAVA) within the L/M pigment genes can result in loss of an entire class of cone photoreceptor, leading to dichromacy.2,3 This provides a potential mechanism whereby the color vision defect and the cone dysfunction can have a common origin. Recently similar variants (LIAVA or LVAVA) were found in all but one BED family investigated.4 Here we used adaptive optics imaging to examine 2 brothers with BED harboring the LIAVA polymorphisms. Interestingly, they each had variably disrupted cone mosaics, with the degree of disruption correlating to the degree of cone dysfunction. Thus, while polymorphic opsin variants such as LIAVA will always lead to a degree of reduced cone function (including dichromacy), whether they lead to generalized cone dysfunction and high myopia may depend on the relative number of cones expressing the aberrant pigment. Michaelides et al. (2004) stated that in BED, “other genetic factors...within which the primary disease causing mutation is expressed may determine the final phenotype”.5 Our anatomical data indicate that these “other factors” could include genes or sequences that affect L:M cone ratio,6,7 which is known to be highly variable.8,9