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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2023
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.
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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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