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Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant
The Emory cataract (Em) mouse mutant has long been proposed as an animal model for age-related or senile cataract in humans—a leading cause of visual impairment. However, the genetic defect(s) underlying the autosomal dominant Em phenotype remains elusive. Here, we confirmed development of the catar...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151407/ https://www.ncbi.nlm.nih.gov/pubmed/36891866 http://dx.doi.org/10.1093/g3journal/jkad055 |
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author | Bennett, Thomas M Zhou, Yuefang Meyer, Kacie J Anderson, Michael G Shiels, Alan |
author_facet | Bennett, Thomas M Zhou, Yuefang Meyer, Kacie J Anderson, Michael G Shiels, Alan |
author_sort | Bennett, Thomas M |
collection | PubMed |
description | The Emory cataract (Em) mouse mutant has long been proposed as an animal model for age-related or senile cataract in humans—a leading cause of visual impairment. However, the genetic defect(s) underlying the autosomal dominant Em phenotype remains elusive. Here, we confirmed development of the cataract phenotype in commercially available Em/J mice [but not ancestral Carworth Farms White (CFW) mice] at 6–8 months of age and undertook whole-exome sequencing of candidate genes for Em. Analysis of coding and splice-site variants did not identify any disease-causing/associated mutations in over 450 genes known to underlie inherited and age-related forms of cataract and other lens disorders in humans and mice, including genes for lens crystallins, membrane/cytoskeleton proteins, DNA/RNA-binding proteins, and those associated with syndromic/systemic forms of cataract. However, we identified three cataract/lens-associated genes each with one novel homozygous variant including predicted missense substitutions in Prx (p.R167C) and Adamts10 (p.P761L) and a disruptive in-frame deletion variant (predicted missense) in Abhd12 (p.L30_A32delinsS) that were absent in CFW and over 35 other mouse strains. In silico analysis predicted that the missense substitutions in Prx and Adamts10 were borderline neutral/damaging and neutral, respectively, at the protein function level, whereas, that in Abhd12 was functionally damaging. Both the human counterparts of Adamts10 and Abhd12 are clinically associated with syndromic forms of cataract known as Weil-Marchesani syndrome 1 and polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome, respectively. Overall, while we cannot exclude Prx and Adamts10, our data suggest that Abhd12 is a promising candidate gene for cataract in the Em/J mouse. |
format | Online Article Text |
id | pubmed-10151407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101514072023-05-03 Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant Bennett, Thomas M Zhou, Yuefang Meyer, Kacie J Anderson, Michael G Shiels, Alan G3 (Bethesda) Mutant Screen Report The Emory cataract (Em) mouse mutant has long been proposed as an animal model for age-related or senile cataract in humans—a leading cause of visual impairment. However, the genetic defect(s) underlying the autosomal dominant Em phenotype remains elusive. Here, we confirmed development of the cataract phenotype in commercially available Em/J mice [but not ancestral Carworth Farms White (CFW) mice] at 6–8 months of age and undertook whole-exome sequencing of candidate genes for Em. Analysis of coding and splice-site variants did not identify any disease-causing/associated mutations in over 450 genes known to underlie inherited and age-related forms of cataract and other lens disorders in humans and mice, including genes for lens crystallins, membrane/cytoskeleton proteins, DNA/RNA-binding proteins, and those associated with syndromic/systemic forms of cataract. However, we identified three cataract/lens-associated genes each with one novel homozygous variant including predicted missense substitutions in Prx (p.R167C) and Adamts10 (p.P761L) and a disruptive in-frame deletion variant (predicted missense) in Abhd12 (p.L30_A32delinsS) that were absent in CFW and over 35 other mouse strains. In silico analysis predicted that the missense substitutions in Prx and Adamts10 were borderline neutral/damaging and neutral, respectively, at the protein function level, whereas, that in Abhd12 was functionally damaging. Both the human counterparts of Adamts10 and Abhd12 are clinically associated with syndromic forms of cataract known as Weil-Marchesani syndrome 1 and polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome, respectively. Overall, while we cannot exclude Prx and Adamts10, our data suggest that Abhd12 is a promising candidate gene for cataract in the Em/J mouse. Oxford University Press 2023-03-09 /pmc/articles/PMC10151407/ /pubmed/36891866 http://dx.doi.org/10.1093/g3journal/jkad055 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Mutant Screen Report Bennett, Thomas M Zhou, Yuefang Meyer, Kacie J Anderson, Michael G Shiels, Alan Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title | Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title_full | Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title_fullStr | Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title_full_unstemmed | Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title_short | Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant |
title_sort | whole-exome sequencing prioritizes candidate genes for hereditary cataract in the emory mouse mutant |
topic | Mutant Screen Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151407/ https://www.ncbi.nlm.nih.gov/pubmed/36891866 http://dx.doi.org/10.1093/g3journal/jkad055 |
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