March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Combined Exome Sequencing And Linkage Analysis Reveals A Dominant-negative ZNF408 Mutation Causing Familial Exudative Vitreoretinopathy
Author Affiliations & Notes
  • Rob W. Collin
    Human Genetics,
    Ophthalmology,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Konstantinos Nikopoulos
    Human Genetics,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Christian Gilissen
    Human Genetics,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • F Nienke Boonstra
    Bartimeus Institute for the Visually Impaired, Zeist, The Netherlands
  • Hiroyuki Kondo
    Department of Ophthalmology, Univ of Occupatn'l & Environmntl H, Kitakyushu, Japan
  • Carmel Toomes
    Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
  • Wolfgang Berger
    Institute of Medical Molecular Genetics, University of Zurich, Schwerzenbach, Switzerland
  • C Erik van Nouhuys
    Ophthalmology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
  • Alexander Hoischen
    Human Genetics,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Frans P. Cremers
    Human Genetics,
    Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  • Footnotes
    Commercial Relationships  Rob W. Collin, None; Konstantinos Nikopoulos, None; Christian Gilissen, None; F Nienke Boonstra, None; Hiroyuki Kondo, None; Carmel Toomes, None; Wolfgang Berger, None; C Erik van Nouhuys, None; Alexander Hoischen, None; Frans P. Cremers, None
  • Footnotes
    Support  European Union Research Training Network grant RETNET (MRTN-CT-2003-5040032); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Landelijke Stichting voor Blinden en Slechtzienden
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2257. doi:
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      Rob W. Collin, Konstantinos Nikopoulos, Christian Gilissen, F Nienke Boonstra, Hiroyuki Kondo, Carmel Toomes, Wolfgang Berger, C Erik van Nouhuys, Alexander Hoischen, Frans P. Cremers; Combined Exome Sequencing And Linkage Analysis Reveals A Dominant-negative ZNF408 Mutation Causing Familial Exudative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2257.

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

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Abstract

Purpose: : To identify the genetic defect underlying autosomal dominant familial exudative vitreoretinopathy (FEVR) in a large Dutch pedigree.

Methods: : Affected family members were genotyped using 6k SNP arrays, followed by linkage analysis. Two distantly related patients were analyzed by exome sequencing. Candidate variants were validated and segregation analysis was performed in the complete family. Upon identification of a causative missense mutation in ZNF408, this gene was screened in a cohort of 132 additional FEVR probands. Subsequently, cDNA constructs expressing wild-type and mutant ZNF408 proteins were generated for immunolocalization studies in COS-1 cells. The tissue distribution of ZNF408 was studied via real-time quantitative RT-PCR analysis.

Results: : Combining exome sequencing, linkage analysis and segregation analysis revealed a single probable disease-causing missense mutation in ZNF408 (c.1363C>T; p.His455Tyr), which was also detected in an additional Dutch FEVR family. Sequence analysis of ZNF408 in 132 additional FEVR patients revealed a second missense variant (p.Ser126Asn). Immunolocalisation analysis revealed that the wild-type, and the p.Ser126Asn mutant protein show a complete nuclear localization, whereas the p.His455Tyr mutant protein was localized almost exclusively in the cytoplasm. Moreover, in a co-transfection assay, the p.His455Tyr mutant protein retains the wild-type ZNF408 protein in the cytoplasm, suggesting a dominant-negative effect of the p.His455Tyr mutation. ZNF408 was found to be abundantly expressed in the retina.

Conclusions: : Together, our data strongly suggest that ZNF408 is implicated in adFEVR, thereby revealing a transcription factor that may act in the norrin/β-catenin signaling pathway.

Keywords: genetics • mutations • gene mapping 
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