UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

King, R; Struebing, FL; Li, Y; Wang, J; Koch, AA; Cooke Bailey, JN; Gharahkhani, P; ... Geisert, EE; + view all (2018) Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genetics , 14 (1) , Article e1007145. 10.1371/journal.pgen.1007145. Green open access

[thumbnail of Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.pdf]
Preview
Text
Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.pdf - Published Version

Download (13MB) | Preview

Abstract

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.

Type: Article
Title: Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1007145
Publisher version: https://doi.org/10.1371/journal.pgen.1007145
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Animals, Apoptosis, Cells, Cultured, Chromosome Mapping, Cornea, Corneal Pachymetry, Disease Models, Animal, Embryo, Mammalian, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, POU Domain Factors, Polymorphism, Single Nucleotide, Pregnancy, Retinal Ganglion Cells, Risk Factors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/10055399
Downloads since deposit
65Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item