Congenital Cataract in Gpr161vl/vl Mice Is Modified by Proximal Chromosome 15

Bo I Li,Myka R Ababon,Vikas Nanda,Paul G Matteson,James H Millonig,Yong Lin,Michael G Anderson

doi:10.1371/journal.pone.0170724

Bo I Li, Myka R Ababon + Show 5 more

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https://doi.org/10.1371/journal.pone.0170724

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Abstract

The morphology and severity of human congenital cataract varies even among individuals with the same mutation, suggesting that genetic background modifies phenotypic penetrance. The spontaneous mouse mutant, vacuolated lens (vl), arose on the C3H/HeSnJ background. The mutation disrupts secondary lens fiber development by E16.5, leading to full penetrance of congenital cataract. The vl locus was mapped to a frameshift deletion in the orphan G protein-coupled receptor, Gpr161, which is expressed in differentiating lens fiber cells. When Gpr161vl/vl C3H mice are crossed to MOLF/EiJ mice an unexpected rescue of cataract is observed, suggesting that MOLF modifiers affect cataract penetrance. Subsequent QTL analysis mapped three modifiers (Modvl3-5: Modifier of vl) and in this study we characterized Modvl4 (Chr15; LOD = 4.4). A Modvl4MOLF congenic was generated and is sufficient to rescue congenital cataract and the lens fiber defect at E16.5. Additional phenotypic analysis on three subcongenic lines narrowed down the interval from 55 to 15Mb. In total only 18 protein-coding genes and 2 micro-RNAs are in this region. Fifteen of the 20 genes show detectable expression in the E16.5 eye. Subsequent expression studies in Gpr161vl/vl and subcongenic E16.5 eyes, bioinformatics analysis of C3H/MOLF polymorphisms, and the biological relevancy of the genes in the interval identified three genes (Cdh6, Ank and Trio) that likely contribute to the rescue of the lens phenotype. These studies demonstrate that modification of the Gpr161vl/vl cataract phenotype is likely due to genetic variants in at least one of three closely linked candidate genes on proximal Chr15.

Highlights

Congenital cataract is the presence of an opacity in the lens at birth, affecting approximately 3 out of 10,000 live births in United States [1]
The male mice with the most contribution to the C3H background but were still C3H/MOLF for the Modvl4 Quantitative Trait Locus (QTL) 95% CI were selected for further backcrossing until the congenic (Modvl4C/M) was generated (S1 Fig, panel A)
These results suggest that unlinked genetic variants can contribute to the modification of the primary mutation

Summary

Introduction

Congenital cataract is the presence of an opacity in the lens at birth, affecting approximately 3 out of 10,000 live births in United States [1]. Similar to other birth defects, congenital cataract has a genetic basis with approximately 30–50% of the disorder being transmissible [2]. The same genetic mutation in different families can affect the penetrance or severity of the congenital cataract, suggesting that additional genes or environmental factors can modify the primary mutation [3, 7, 8]. Mouse mutant models of congenital cataract have significantly contributed to our understanding of the disorder at a molecular level. Whether genetic variation can modify the penetrance and severity of mouse congenital cataract remains to be determined. We present the first multi-genic mouse model of congenital cataract

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