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Masakazu Akahori, Kazushige Tsunoda, Yozo Miyake, Shoji Tsuji, Tomoaki Usui, Makoto Nakamura, Hisao Ohde, Takeshi Itabashi, Takeshi Iwata; Dominant Mutations In RP1L1 Are Responsible For Occult Macular Dystrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5385.
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Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina.
Linkage analysis of two OMD families was performed by Affymetrix SNP 6.0 array and the SNP High Throughput Linkage analysis system (SNP HiTLink). Coding exons of four protein coding genes in the candidate region were analyzed for sequence variations by direct DNA-sequencing. Immuno-staining for RP1L1 was carried out on frozen sections of normal cynomolgus and paraffin section of normal marmoset.
Genome wide linkage analysis localized the disease locus to chromosome 8p22-p23. Among the 128 genes in the associated region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1), however, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but none in 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus and marmoset monkey revealed expression in the inner segment of rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD.
Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.
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