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Disease mechanisms of X-linked cone dystrophy caused by missense mutations in the red and green cone opsins.
Zhu, Ping; Dyka, Frank; Ma, Xiaojie; Yin, Ling; Yu, Heather; Baehr, Wolfgang; Hauswirth, William W; Deng, Wen-Tao.
Afiliación
  • Zhu P; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
  • Dyka F; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
  • Ma X; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
  • Yin L; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
  • Yu H; Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
  • Baehr W; Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, Utah, USA.
  • Hauswirth WW; Department of Neurobiology and Anatomy, University of Utah Health Science Center, Salt Lake City, Utah, USA.
  • Deng WT; Department of Biology, University of Utah, Salt Lake City, Utah, USA.
FASEB J ; 35(10): e21927, 2021 10.
Article en En | MEDLINE | ID: mdl-34547123
Cone photoreceptors are responsible for the visual acuity and color vision of the human eye. Red/green cone opsin missense mutations N94K, W177R, P307L, R330Q, and G338E have been identified in subjects with congenital blue cone monochromacy or color-vision deficiency. Studies on disease mechanisms due to these cone opsin mutations have been previously carried out exclusively in vitro, and the reported impairments were not always consistent. Here we expressed these mutants via AAV specifically in vivo in M-opsin knockout mouse cones to investigate their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. We show that these mutations alter the M-opsin structure, function, and localization. N94K and W177R mutants appeared to be misfolded since they localized exclusively in cone inner segments and endoplasmic reticulum. In contrast, P307L, R330Q, and G338E mutants were detected predominately in cone outer segments. Expression of R330Q and G338E, but not P307L opsins, also partially restored expression and correct localization of cone PDE6α' and cone transducin γ and resulted in partial rescue of M-cone-mediated light responses. Expression of W177R and P307L mutants significantly reduced cone viability, whereas N94K, R330Q, and G338E were only modestly toxic. We propose that although the underlying biochemical and cellular defects caused by these mutants are distinct, they all seem to exhibit a dominant phenotype, resembling autosomal dominant retinitis pigmentosa associated with the majority of rhodopsin missense mutations. The understanding of the molecular mechanisms associated with these cone opsin mutants is fundamental to developing targeted therapies for cone dystrophy/dysfunction.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Mutación Missense / Genes Ligados a X / Opsinas de los Conos / Distrofia del Cono Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Mutación Missense / Genes Ligados a X / Opsinas de los Conos / Distrofia del Cono Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos