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A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects
PURPOSE: We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. MET...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Association for Research in Vision and Ophthalmology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599165/ https://www.ncbi.nlm.nih.gov/pubmed/37862028 http://dx.doi.org/10.1167/iovs.64.13.32 |
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author | Guardia, Ana Fernández, Almudena Seruggia, Davide Chotard, Virginie Sánchez-Castillo, Carla Kutsyr, Oksana Sánchez-Sáez, Xavier Zurita, Esther Cantero, Marta Rebsam, Alexandra Cuenca, Nicolás Montoliu, Lluís |
author_facet | Guardia, Ana Fernández, Almudena Seruggia, Davide Chotard, Virginie Sánchez-Castillo, Carla Kutsyr, Oksana Sánchez-Sáez, Xavier Zurita, Esther Cantero, Marta Rebsam, Alexandra Cuenca, Nicolás Montoliu, Lluís |
author_sort | Guardia, Ana |
collection | PubMed |
description | PURPOSE: We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. METHODS: The FHONDA mouse model was generated with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology using an RNA guide targeting the Scl38a8 murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT). RESULTS: From numerous Slc38a8 mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*). Slc38a8 mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin content. Subcellular abnormalities were observed in retinal pigment epithelium cells of Slc38a8 mutant mice. Anterograde labeling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT. CONCLUSIONS: Slc38a8 mutant mice recapitulate the phenotype of patients with FHONDA concerning their normal pigmentation and their abnormal visual system, in the latter being a hallmark of all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition. |
format | Online Article Text |
id | pubmed-10599165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
spelling | pubmed-105991652023-10-26 A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects Guardia, Ana Fernández, Almudena Seruggia, Davide Chotard, Virginie Sánchez-Castillo, Carla Kutsyr, Oksana Sánchez-Sáez, Xavier Zurita, Esther Cantero, Marta Rebsam, Alexandra Cuenca, Nicolás Montoliu, Lluís Invest Ophthalmol Vis Sci Genetics PURPOSE: We aimed to generate and phenotype a mouse model of foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA), a rare disease associated with mutations in Slc38a8 that causes severe visual alterations similar to albinism without affecting pigmentation. METHODS: The FHONDA mouse model was generated with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology using an RNA guide targeting the Scl38a8 murine locus. The resulting mice were backcrossed to C57BL/6J. Melanin content was measured using spectrophotometry. Retinal cell architecture was analyzed through light and electron microscopy. Retinal projections to the brain were evaluated with anterograde labelling in embryos and adults. Visual function was assessed by electroretinography (ERG) and the optomotor test (OT). RESULTS: From numerous Slc38a8 mouse mutant alleles generated, we selected one that encodes a truncated protein (p.196Pro*, equivalent to p.199Pro* in the human protein) closely resembling a mutant allele described in patients (p.200Gln*). Slc38a8 mutant mice exhibit wild-type eye and coat pigmentation with comparable melanin content. Subcellular abnormalities were observed in retinal pigment epithelium cells of Slc38a8 mutant mice. Anterograde labeling experiments of retinal projections in embryos and adults showed a reduction of ipsilateral fibers. Functional visual analyses revealed a decreased ERG response in scotopic conditions and a reduction of visual acuity in mutant mice measured by OT. CONCLUSIONS: Slc38a8 mutant mice recapitulate the phenotype of patients with FHONDA concerning their normal pigmentation and their abnormal visual system, in the latter being a hallmark of all types of albinism. These mice will be helpful in better understanding the pathophysiology of this genetic condition. The Association for Research in Vision and Ophthalmology 2023-10-20 /pmc/articles/PMC10599165/ /pubmed/37862028 http://dx.doi.org/10.1167/iovs.64.13.32 Text en Copyright 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
spellingShingle | Genetics Guardia, Ana Fernández, Almudena Seruggia, Davide Chotard, Virginie Sánchez-Castillo, Carla Kutsyr, Oksana Sánchez-Sáez, Xavier Zurita, Esther Cantero, Marta Rebsam, Alexandra Cuenca, Nicolás Montoliu, Lluís A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title | A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title_full | A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title_fullStr | A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title_full_unstemmed | A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title_short | A Slc38a8 Mouse Model of FHONDA Syndrome Faithfully Recapitulates the Visual Deficits of Albinism Without Pigmentation Defects |
title_sort | slc38a8 mouse model of fhonda syndrome faithfully recapitulates the visual deficits of albinism without pigmentation defects |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599165/ https://www.ncbi.nlm.nih.gov/pubmed/37862028 http://dx.doi.org/10.1167/iovs.64.13.32 |
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