title: Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.
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.
authors.affiliation: 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.
authors.forename: Almudena
authors.initials: A
authors.lastname: Avila-Fernandez
authors.affiliation: 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.
authors.forename: Raquel
authors.initials: R
authors.lastname: Perez-Carro
authors.affiliation: 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.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: Department of Ophthalmology, IIS-Fundacion Jimenez Diaz University Hospital, Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Lopez-Molina
authors.affiliation: Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Campello
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garanto
authors.affiliation: Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Fernandez-Sanchez
authors.affiliation: Department of Human Genetics.
authors.forename: Lonneke
authors.initials: L
authors.lastname: Duijkers
authors.affiliation: 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.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Lopez-Martinez
authors.affiliation: 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.
authors.forename: Rosa
authors.initials: R
authors.lastname: Riveiro-Alvarez
authors.affiliation: 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.
authors.forename: Luciana Rodrigues Jacy
authors.initials: LR
authors.lastname: Da Silva
authors.affiliation: 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.
authors.forename: Rocío
authors.initials: R
authors.lastname: Sanchez-Alcudia
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Martin-Garrido
authors.affiliation: 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.
authors.forename: Noelia
authors.initials: N
authors.lastname: Reyes
authors.affiliation: 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.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia-Garcia
authors.affiliation: 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.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Department of Ophthalmology, IIS-Fundacion Jimenez Diaz University Hospital, Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Garcia-Sandoval
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cuenca
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D012160:Retina / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D014157:Transcription Factors; C582974:ZNF408 protein, human