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Arif Khan, Shahid Khan, Zhiwei Ma, Saleh Al-Mesfer, Shahira Al Turkmani, Sheikh Riazuddin, Walter Stark, James Hejtmancik, John Gottsch, S. Amer Riazuddin; Functional characterization of a homozygous nonsense FOXE3 mutation that causes Peters anomaly in a consanguineous family. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1352. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Peters anomaly is a congenital anterior segment dysgenesis characterized by central corneal opacity, posterior corneal defect, and irido-lenticular adhesions. As part of our ongoing investigation of the genetics of Peters anomaly, we report an underlying recessive mutation in an affected consanguineous family and its functional characterization.
A consanguineous family with familial Peters anomaly (four affected individuals) was ascertained. Blood samples were collected and genomic DNA was extracted from white blood cells using a non-organic method. A genome-wide linkage scan was completed to localize the disease phenotype and two-point LOD scores were calculated. The causative mutation was identified by bi-directional Sanger sequencing of candidate genes present in the linkage interval. A standard immunofluorescence staining protocol was used to localize the mutant protein in HeLa cells.
Affected individuals had clinical Peters anomaly (bilateral corneal opacities, irido-lenticular adhesions) and developmental glaucoma. Genome-wide linkage analysis identified an informative homozygous region on chromosome 1p with significant two-point LOD scores. Bi-directional Sanger sequencing of candidate genes on chromosome 1p identified a homozygous substitution (c.720C>A; p.C240X) present in all four affected individuals. The 11 unaffected individuals were heterozygous carriers (nine) or were homozygous for the wild type allele (two). This variant is predicted to prematurely truncate the FOXE3 protein and was absent in 192 ethnically matched control chromosomes. Immunofluorescence tracking confirmed nuclear localization of the mutant protein similar to that of the wild type FOXE3 protein.
Our data strongly suggest that homozygous nonsense mutation in FOXE3 causes Peters anomaly and subsequent in vivo analyses confirm that the mutation does not affect the localization of FOXE3 protein to the nucleus. We speculate that premature termination of FOXE3 compromises its ability to regulate genes critical for ocular developmental leading to the disease phenotype.
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