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Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal ar...

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Autores principales: Toral, Marcus A., Velez, Gabriel, Boudreault, Katherine, Schaefer, Kellie A., Xu, Yu, Saffra, Norman, Bassuk, Alexander G., Tsang, Stephen H., Mahajan, Vinit B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441399/
https://www.ncbi.nlm.nih.gov/pubmed/28546991
http://dx.doi.org/10.1002/mgg3.266
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author Toral, Marcus A.
Velez, Gabriel
Boudreault, Katherine
Schaefer, Kellie A.
Xu, Yu
Saffra, Norman
Bassuk, Alexander G.
Tsang, Stephen H.
Mahajan, Vinit B.
author_facet Toral, Marcus A.
Velez, Gabriel
Boudreault, Katherine
Schaefer, Kellie A.
Xu, Yu
Saffra, Norman
Bassuk, Alexander G.
Tsang, Stephen H.
Mahajan, Vinit B.
author_sort Toral, Marcus A.
collection PubMed
description BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium‐coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT‐angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations. METHODS: Fundus autofluorescence, SD‐OCT, and OCT‐angiography were used to make the clinical diagnosis. Whole‐exome sequencing led to the identification of a novel disease‐causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function. RESULTS: We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT‐angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore. CONCLUSION: Our results demonstrate a novel use for OCT‐angiography in confirming FH, and also uncover genotype–phenotype correlations of FH‐linked SLC38A8 mutations.
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spelling pubmed-54413992017-05-25 Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia Toral, Marcus A. Velez, Gabriel Boudreault, Katherine Schaefer, Kellie A. Xu, Yu Saffra, Norman Bassuk, Alexander G. Tsang, Stephen H. Mahajan, Vinit B. Mol Genet Genomic Med Original Articles BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium‐coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT‐angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations. METHODS: Fundus autofluorescence, SD‐OCT, and OCT‐angiography were used to make the clinical diagnosis. Whole‐exome sequencing led to the identification of a novel disease‐causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function. RESULTS: We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT‐angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore. CONCLUSION: Our results demonstrate a novel use for OCT‐angiography in confirming FH, and also uncover genotype–phenotype correlations of FH‐linked SLC38A8 mutations. John Wiley and Sons Inc. 2017-02-26 /pmc/articles/PMC5441399/ /pubmed/28546991 http://dx.doi.org/10.1002/mgg3.266 Text en © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Toral, Marcus A.
Velez, Gabriel
Boudreault, Katherine
Schaefer, Kellie A.
Xu, Yu
Saffra, Norman
Bassuk, Alexander G.
Tsang, Stephen H.
Mahajan, Vinit B.
Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title_full Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title_fullStr Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title_full_unstemmed Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title_short Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
title_sort structural modeling of a novel slc38a8 mutation that causes foveal hypoplasia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441399/
https://www.ncbi.nlm.nih.gov/pubmed/28546991
http://dx.doi.org/10.1002/mgg3.266
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