title: Congenital Cataract in Gpr161vl/vl Mice Is Modified by Proximal Chromosome 15.
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.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Bo I
authors.initials: BI
authors.lastname: Li
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States of America.|Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Myka R
authors.initials: MR
authors.lastname: Ababon
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States of America.|Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Matteson
authors.affiliation: Division of Biometrics, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States of America.|Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Biochemistry, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Vikas
authors.initials: V
authors.lastname: Nanda
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Neuroscience and Cell Biology, Rutgers University, Piscataway, New Jersey, United States of America.|Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.|Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Millonig
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D002454:Cell Differentiation; D033481:Chromosomes, Mammalian / Q000378:metabolism*; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D056726:Genetic Association Studies; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D058977:Molecular Sequence Annotation; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism
chemical_list: C533095:GPR161 protein, mouse; D043562:Receptors, G-Protein-Coupled