Dataset Information

Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.

ABSTRACT: Applying CNGA3 gene augmentation therapy to cure a novel causative mutation underlying achromatopsia (ACHM) in sheep.Impaired vision that spontaneously appeared in newborn lambs was characterized by behavioral, electroretinographic (ERG), and histologic techniques. Deep-sequencing reads of an affected lamb and an unaffected lamb were compared within conserved genomic regions orthologous to human genes involved in similar visual impairment. Observed nonsynonymous amino acid substitutions were classified by their deleteriousness score. The putative causative mutation was assessed by producing compound CNGA3 heterozygotes and applying gene augmentation therapy using the orthologous human cDNA.Behavioral assessment revealed day blindness, and subsequent ERG examination showed attenuated photopic responses. Histologic and immunohistochemical examination of affected sheep eyes did not reveal degeneration, and cone photoreceptors expressing CNGA3 were present. Bioinformatics and sequencing analyses suggested a c.1618G>A, p.Gly540Ser substitution in the GMP-binding domain of CNGA3 as the causative mutation. This was confirmed by genetic concordance test and by genetic complementation experiment: All five compound CNGA3 heterozygotes, carrying both p.Arg236* and p.Gly540Ser mutations in CNGA3, were day-blind. Furthermore, subretinal delivery of the intact human CNGA3 gene using an adeno-associated viral vector (AAV) restored photopic vision in two affected p.Gly540Ser homozygous rams.The c.1618G>A, p.Gly540Ser substitution in CNGA3 was identified as the causative mutation for a novel form of ACHM in Awassi sheep. Gene augmentation therapy restored vision in the affected sheep. This novel mutation provides a large-animal model that is valid for most human CNGA3 ACHM patients; the majority of them carry missense rather than premature-termination mutations.

SUBMITTER: Gootwine E

PROVIDER: S-EPMC5361581 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.

Gootwine Elisha E Abu-Siam Mazen M Obolensky Alexey A Rosov Alex A Honig Hen H Nitzan Tali T Shirak Andrey A Ezra-Elia Raaya R Yamin Esther E Banin Eyal E Averbukh Edward E Hauswirth William W WW Ofri Ron R Seroussi Eyal E

Investigative ophthalmology & visual science 20170301 3

<h4>Purpose</h4>Applying CNGA3 gene augmentation therapy to cure a novel causative mutation underlying achromatopsia (ACHM) in sheep.<h4>Methods</h4>Impaired vision that spontaneously appeared in newborn lambs was characterized by behavioral, electroretinographic (ERG), and histologic techniques. Deep-sequencing reads of an affected lamb and an unaffected lamb were compared within conserved genomic regions orthologous to human genes involved in similar visual impairment. Observed nonsynonymous a ...[more]

PMID: 28282490

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Project description:Visual speech facilitates auditory speech perception, but the visual cues responsible for these benefits and the information they provide remain unclear. Low-level models emphasize basic temporal cues provided by mouth movements, but these impoverished signals may not fully account for the richness of auditory information provided by visual speech. High-level models posit interactions among abstract categorical (i.e., phonemes/visemes) or amodal (e.g., articulatory) speech representations, but require lossy remapping of speech signals onto abstracted representations. Because visible articulators shape the spectral content of speech, we hypothesized that the perceptual system might exploit natural correlations between midlevel visual (oral deformations) and auditory speech features (frequency modulations) to extract detailed spectrotemporal information from visual speech without employing high-level abstractions. Consistent with this hypothesis, we found that the time-frequency dynamics of oral resonances (formants) could be predicted with unexpectedly high precision from the changing shape of the mouth during speech. When isolated from other speech cues, speech-based shape deformations improved perceptual sensitivity for corresponding frequency modulations, suggesting that listeners could exploit this cross-modal correspondence to facilitate perception. To test whether this type of correspondence could improve speech comprehension, we selectively degraded the spectral or temporal dimensions of auditory sentence spectrograms to assess how well visual speech facilitated comprehension under each degradation condition. Visual speech produced drastically larger enhancements during spectral degradation, suggesting a condition-specific facilitation effect driven by cross-modal recovery of auditory speech spectra. The perceptual system may therefore use audiovisual correlations rooted in oral acoustics to extract detailed spectrotemporal information from visual speech.

Dataset Information

Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.

Publications

Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.

Similar Datasets

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