June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Functional characterization of a homozygous nonsense FOXE3 mutation that causes Peters anomaly in a consanguineous family
Author Affiliations & Notes
  • Arif Khan
    Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  • Shahid Khan
    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
  • Zhiwei Ma
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD
  • Saleh Al-Mesfer
    Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  • Shahira Al Turkmani
    Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  • Sheikh Riazuddin
    National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
  • Walter Stark
    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
  • James Hejtmancik
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, MD
  • John Gottsch
    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
  • S. Amer Riazuddin
    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD
  • Footnotes
    Commercial Relationships Arif Khan, None; Shahid Khan, None; Zhiwei Ma, None; Saleh Al-Mesfer, None; Shahira Al Turkmani, None; Sheikh Riazuddin, None; Walter Stark, VueCare (C); James Hejtmancik, None; John Gottsch, None; S. Amer Riazuddin, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1352. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

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.

 
Methods
 

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.

 
Results
 

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.

 
Conclusions
 

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.

  
Keywords: 539 genetics • 534 gene mapping • 421 anterior segment  
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