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ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease.
Strayve, Daniel; Makia, Mustafa S; Kakakhel, Mashal; Sakthivel, Haarthi; Conley, Shannon M; Al-Ubaidi, Muayyad R; Naash, Muna I.
Afiliación
  • Strayve D; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
  • Makia MS; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
  • Kakakhel M; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
  • Sakthivel H; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
  • Conley SM; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • Al-Ubaidi MR; Oklahoma Center for Neurosciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • Naash MI; Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA.
Hum Mol Genet ; 29(16): 2708-2722, 2020 09 29.
Article en En | MEDLINE | ID: mdl-32716032
Peripherin 2 (PRPH2) is a retina-specific tetraspanin protein essential for the formation of rod and cone photoreceptor outer segments (OS). Patients with mutations in PRPH2 exhibit severe retinal degeneration characterized by vast inter- and intra-familial phenotypic heterogeneity. To help understand contributors to this within-mutation disease variability, we asked whether the PRPH2 binding partner rod OS membrane protein 1 (ROM1) could serve as a phenotypic modifier. We utilized knockin and transgenic mouse models to evaluate the structural, functional and biochemical effects of eliminating one allele of Rom1 (Rom1+/-) in three different Prph2 models which mimic human disease: C213Y Prph2 (Prph2C/+), K153Del Prph2 (Prph2K/+) and R172W (Prph2R172W). Reducing Rom1 in the absence of Prph2 mutations (Rom1+/-) had no effect on retinal structure or function. However, the effects of reducing Rom1 in the presence of Prph2 mutations were highly variable. Prph2K/+/Rom1+/- mice had improved rod and cone function compared with Prph2K/+ as well as amelioration of K153Del-associated defects in PRPH2/ROM1 oligomerization. In contrast, Prph2R172W/Rom1+/- animals had worsened rod and cone function and exacerbated retinal degeneration compared with Prph2R172W animals. Removing one allele of Rom1 had no effect in Prph2C/+. Combined, our findings support a role for non-pathogenic ROM1 null variants in contributing to phenotypic variability in mutant PRPH2-associated retinal degeneration. Since the effects of Rom1 reduction are variable, our data suggest that this contribution is specific to the type of Prph2 mutation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Proteínas del Ojo / Tetraspaninas / Periferinas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Proteínas del Ojo / Tetraspaninas / Periferinas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido