Two diagnoses you never want to hear from the eye doctor are macular degeneration and retinitis pigmentosa. Both are genetic disorders that can cause loss of vision and neither has a cure. A team of biomedical researchers at the University of Houston is now tackling both eye diseases by exploring a protein in the retina that links them: peripherin2 (prph2). Mutations in peripherin 2 are associated with a variety of retinal degenerative diseases, including retinitis pigmentosa, cone-rod dystrophy and multiple forms of macular dystrophy. Peripherin2 mutations can also cause secondary defects in adjacent tissues including the retinal pigment epithelium and choroid, which hampers the development of therapeutics for these diseases. When healthy, prph2 is essential for the structure and function of the outer segments of the retinal photoreceptors. The two types of photoreceptors involved in sight are rods, which work at low levels of light, and cones, which they eye uses to see colors.
Damaged rods cause retinitis pigmentosa; degeneration of cones causes macular degeneration. Prph2 does not always work alone: it has a partner, a photoreceptor-specific gene called ROM1 (rod outer segment membrane protein 1). The two proteins combine in different ratios, subsequently causing different diseases. Muna Naash, Professor of Biomedical engineering and principal investigator, led the research and explained: “We found we could convert the pattern dystrophy or macular degeneration phenotype to retinitis pigmentosa phenotype by modulating ROM1 level. Now we are focused on advancing current knowledge on the role of peripherin2 in outer segment rim and disc formation, and in understanding the pathogenic mechanisms of associated diseases. Peripherin2 is an incredibly exciting protein to study and understand because, depending on which part of the protein has a mutation, it can cause different phenotypes in each patient”.
In prior research, Naash found that by changing the ratio of prph2 and ROM1 she could convert cases of the more dangerous macular degeneration to the less severe retinitis pigmentosa. In 2017, they found that ROM1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa. In vitro, Y141C-Prph2 showed signs of retention in the endoplasmic reticulum (ER), the cellular store where proteins are processed and redirected for proper cellular destination. But, if ROM1 is present this anomaly can be rescued. This suggests that elimination of the mutant protein will be a pre-requisite for any curative therapeutic strategy. The team is examining how different mutations in prph2 lead to different disease phenotypes; what contributes to variability among patients carrying the same mutation; what role ROM1 plays in these events; and, how to shift prph2-associated severe phenotypes to milder ones.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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