Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants

Abstract Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underl...

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Autores principales:	Sybille Böhm, Lisa M. Riedmayr, O. N. Phuong Nguyen, Andreas Gießl, Toni Liebscher, Elisabeth S. Butz, Christian Schön, Stylianos Michalakis, Christian Wahl-Schott, Martin Biel, Elvir Becirovic
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/acb4d448cca04ab194bf7dd125b6ec15
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spelling	oai:doaj.org-article:acb4d448cca04ab194bf7dd125b6ec152021-12-02T15:05:51ZPeripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants10.1038/s41598-017-02514-52045-2322https://doaj.org/article/acb4d448cca04ab194bf7dd125b6ec152017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02514-5https://doaj.org/toc/2045-2322Abstract Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (perWT), mutant peripherin-2 (perMT), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to perWT and Rom-1. Furthermore, both mutants are preferentially forming non-covalent perMT-perMT, perWT-perMT, and Rom-1-perMT dimers. However, only perWT-perMT, but not perMT-perMT or Rom-1-perMT complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent perWT-perMT dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of perWT and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals.Sybille BöhmLisa M. RiedmayrO. N. Phuong NguyenAndreas GießlToni LiebscherElisabeth S. ButzChristian SchönStylianos MichalakisChristian Wahl-SchottMartin BielElvir BecirovicNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sybille Böhm Lisa M. Riedmayr O. N. Phuong Nguyen Andreas Gießl Toni Liebscher Elisabeth S. Butz Christian Schön Stylianos Michalakis Christian Wahl-Schott Martin Biel Elvir Becirovic Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
description	Abstract Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (perWT), mutant peripherin-2 (perMT), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to perWT and Rom-1. Furthermore, both mutants are preferentially forming non-covalent perMT-perMT, perWT-perMT, and Rom-1-perMT dimers. However, only perWT-perMT, but not perMT-perMT or Rom-1-perMT complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent perWT-perMT dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of perWT and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals.
format	article
author	Sybille Böhm Lisa M. Riedmayr O. N. Phuong Nguyen Andreas Gießl Toni Liebscher Elisabeth S. Butz Christian Schön Stylianos Michalakis Christian Wahl-Schott Martin Biel Elvir Becirovic
author_facet	Sybille Böhm Lisa M. Riedmayr O. N. Phuong Nguyen Andreas Gießl Toni Liebscher Elisabeth S. Butz Christian Schön Stylianos Michalakis Christian Wahl-Schott Martin Biel Elvir Becirovic
author_sort	Sybille Böhm
title	Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
title_short	Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
title_full	Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
title_fullStr	Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
title_full_unstemmed	Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
title_sort	peripherin-2 and rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/acb4d448cca04ab194bf7dd125b6ec15
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Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants

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