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Hum Mol Genet. 2015 Jul 15;24(14):4037-48. doi: 10.1093/hmg/ddv140. Epub 2015 Apr 16.

Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.

Author information

1
Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain, Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
2
Department of Ophthalmology, IIS-Fundacion Jimenez Diaz University Hospital, Madrid, Spain.
3
Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
4
Department of Human Genetics, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
5
Department of Human Genetics.
6
Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain, Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain, Universidade de Mogi das Cruzes, São Paulo, Brazil.
7
Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain and Bioinformatics in Rare Diseases (BIER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
8
Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain and Bioinformatics in Rare Diseases (BIER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain, Functional Genomics Node (INB), Valencia, Spain.
9
Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital (IIS-FJD, UAM), Madrid, Spain, Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain, cayuso@fjd.es.

Abstract

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

PMID:
25882705
DOI:
10.1093/hmg/ddv140
[Indexed for MEDLINE]

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