1Univ of Washington, Seattle, Washington
2Medical College of Wisconsin, Milwaukee, Wisconsin
3Flaum Eye Institute, University of Rochester, Rochester, New York
4Crosby Eye Clinic, Crosby, Minnesota
5Ophthalmology, Institute of Ophthalmology, London, United Kingdom
6Duke University Medical Center, Durham, North Carolina
7Moorfields Eye Hospital, London, United Kingdom
Commercial Relationships: Jay Neitz, None; Melissa Wagner-Schuman, None; Alfredo Dubra, None; Stacy A. Sjoberg, None; Anthony T. Moore, None; Terri L. Young, None; Maureen Neitz, None; Joseph Carroll, None; Michel Michaelides, None
Support: RPB, FFS, NIH, Moorfields Special Trustees and the National Institute for Health Research UK, NHS Foundation Trust & UCL Institute of Ophthalmology. AD holds a Burroughs Wellcome Fund Career Award
Purpose:Bornholm Eye Disease (BED) is an X-linked cone dysfunction syndrome with myopia, astigmatism and optic nerve changes. The underlying gene mapped to Xq28, as do the L/M cone opsin genes. We found two combinations of amino acids at the polymorphic positions 153, 171, 174, 178, and 180 encoded by exon 3 of L/M opsin genes that cause cone dysfunction and are never seen in males with normal vision. These combinations, LIAVA and LVAVA, have consistently been found in opsin genes of BED patients. Another mutation, C203R, was found in one family with X-linked cone dysfunction. We investigated the affect of these mutations on the cone mosaics in BED patients.
Methods:7 protanopes from 3 families were recruited from previously reported pedigrees (Michaelides et al., 2005 Ophthal. 112:1448; Young et al., 2004 Arch Ophthal. 122:897). Cone mosaic images were obtained using an adaptive optics ophthalmoscope and/or an adaptive optics scanning laser ophthalmoscope. SD-OCT images were examined for retinal lamination and thickness.
Results:Families with the mutations, LIAVA, LVAVA and C203R were examined. From ocular biometry, the predicted SER ranged from +1D to -11D. Photoreceptor mosaic images revealed significant but variable disruption, with cone density ranging from near normal to reduced by >75%. Retinal thickness was reduced to a variable degree, with some subjects having significant macular thinning and others having normal thickness. Of note, two brothers showed disparate retinal thickness topography and cone mosaic disruption, despite harboring the same mutation, LIAVA.
Conclusions:There was a wide range of photoreceptor mosaic phenotypes. While LIAVA and LVAVA opsins always lead to dysfunction of cones that express them, the degree to which they lead to vision disorder depends on the relative number of cones expressing the aberrant pigment, and on whether the pigment is LVAVA or LIAVA. Michaelides et al. (2004 BJO 88:291) stated that in BED, other genetic factors "within which the primary disease causing mutation is expressed may determine the final phenotype". Our anatomical data indicate that these "other factors" include ones that affect L:M cone ratio, which is known to be highly variable.
Keywords: myopia color pigments and opsins genetics
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