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      Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa

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          Abstract

          Mutations in peripherin 2 ( PRPH2), also known as retinal degeneration slow/ RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP. We asked whether ROM1 could modify the phenotype of a PRPH2 mutation associated with a high degree of intrafamilial phenotypic heterogeneity: Y141C. In vitro, Y141C-Prph2 showed signs of retention in the endoplasmic reticulum (ER), however co-expression with Rom1 rescued this phenotype. In the heterozygous Y141C knockin mouse model ( Prph2 Y/+ ), Y141C-Prph2 and Rom1 formed abnormal complexes but were present at normal levels. Abnormal complexes were eliminated in the absence of Rom1 ( Prph2 Y/+/Rom1 -/- ) and total Prph2 levels were reduced to those found in the haploinsufficient Prph2 +/- RP model. The biochemical changes had functional and structural consequences; while Prph2 Y/+  animals exhibited a cone-rod electroretinogram defect, Prph2 Y/+/Rom1 -/- animals displayed a rod-dominant phenotype and OSs similar to those seen in the Prph2 +/- . These data show that ablation of Rom1 results in the conversion of an MD/PD phenotype characterized by cone functional defects and the formation of abnormal Prph2/Rom1 complexes to an RP phenotype characterized by rod-dominant functional defects and reductions in total Prph2 protein. Thus one method by which ROM1 may act as a disease modifier is by contributing to the large variability in PRPH2-associated disease phenotypes.

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          Author and article information

          Journal
          Hum Mol Genet
          Hum. Mol. Genet
          hmg
          Human Molecular Genetics
          Oxford University Press
          0964-6906
          1460-2083
          01 February 2017
          04 January 2017
          01 February 2018
          : 26
          : 3
          : 509-518
          Affiliations
          [1 ]Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
          [2 ]Department of Biomedical Engineering, University of Houston, Houston, TX, USA
          Author notes
          [* ]To whom correspondence should be addressed at: Muna I. Naash, Ph.D., John S. Dunn Professor of Biomedical Engineering, Department of Biomedical Engineering, University of Houston, 3517 Cullen Blvd. Room 2011, Houston, TX 77204-5060, USA. Tel: 713-743-1651; E-mail: mnaash@ 123456central.uh.edu

          These two authors contributed equally to this work.

          Article
          PMC6075606 PMC6075606 6075606 ddw408
          10.1093/hmg/ddw408
          6075606
          28053051
          © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
          Page count
          Pages: 10
          Funding
          Funded by: National Eye Institute 10.13039/100000053
          Award ID: R01EY010609-MIN
          Funded by: Foundation Fighting Blindness (MIN), the Oklahoma Center for the Advancement of Science and Technology
          Award ID: SMC, HR14-150
          Funded by: Presbyterian Health Foundation (SMC)
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