Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant

Thomas M Bennett; Yuefang Zhou; Kacie J Meyer; Michael G Anderson; Alan Shiels

doi:10.1093/g3journal/jkad055

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Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant

Journal article

Open access

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Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant

Thomas M Bennett, Yuefang Zhou, Kacie J Meyer, Michael G Anderson and Alan Shiels

G3 : genes - genomes - genetics, Vol.13(5), jkad055

05/2023

DOI: 10.1093/g3journal/jkad055

PMCID: PMC10151407

PMID: 36891866

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Abstract

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 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 (PHARC) 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.

cataract

lens

Adamts10

CFW-Em/J mouse

Abhd12

Prx

Details

Title: Subtitle: Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant
Creators: Thomas M Bennett - Visual Sciences
Yuefang Zhou - Visual Sciences
Kacie J Meyer - University of Iowa
Michael G Anderson - University of Iowa
Alan Shiels - Visual Sciences
Resource Type: Journal article
Publication Details: G3 : genes - genomes - genetics, Vol.13(5), jkad055
DOI: 10.1093/g3journal/jkad055
PMID: 36891866
PMCID: PMC10151407
NLM abbreviation: G3 (Bethesda)
ISSN: 2160-1836
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: EY012284, EY018825, EY02687; name: Core Grant for Vision Research; DOI: 10.13039/100001818, name: Research to Prevent Blindness
Language: English
Electronic publication date: 03/09/2023
Date published: 05/2023
Academic Unit: Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
Record Identifier: 9984375350502771

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