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Abstract
Choroideremia (CHM) and Malattia Leventinese (ML) are two inherited forms of retinal degeneration that involve pathology of the retinal pigment epithelium (RPE). CHM is an X-linked recessive disease marked by peripheral vision loss, while ML is a dominantly-inherited disease marked by central vision loss. Many of the pathological changes in ML also occur in age-related macular degeneration (AMD). Despite the available clinical data, which suggest that both diseases initiate in or near the RPE, very little is known about the mechanisms or the progression of these diseases at the molecular level. In order to address this issue, the expression profiles of Chm and Efemp1 , the genes affected in CHM and ML, respectively, were studied in the mouse retina at different stages of ocular development. In addition, a CHM patient with no molecular signs of the disease was further evaluated for the presence of unique genetic alterations. Finally, the secretion properties of the protein mutated in ML, EFEMP1, were evaluated in polarized RPE cells. Results of the expression studies showed that both Chm and Efemp1 were expressed in a broad pattern in the eye, in many retinal cell types of the mouse throughout development, including the cells of the inner retina and the RPE. Molecular analysis of the CHM patient showed numerous genomic sequence differences upstream of the CHM gene and vastly reduced levels of CHM mRNA. Secretion analysis showed that both the wild-type and mutant EFEMP1 proteins were basolaterally secreted, but also that the mutant protein accumulates intracellularly. The results of these studies indicated that choroideremia may be caused by global retinal defects, not only by defects in the RPE, and that low expression levels of the CHM gene may be responsible for disease in some patients. The EFEMP1 gene, which is affected in ML, may have important functions throughout the retina, but the accumulation of the mutant EFEMP1 protein within the RPE likely contributes directly to the initiation of this disease.
