title: A mutation in ZNF513, a putative regulator of photoreceptor development, causes autosomal-recessive retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a phenotypically and genetically heterogeneous group of inherited retinal degenerations characterized clinically by night blindness, progressive constriction of the visual fields, and loss of vision, and pathologically by progressive loss of rod and then cone photoreceptors. Autosomal-recessive RP (arRP) in a consanguineous Pakistani family previously linked to chromosome 2p22.3-p24.1 is shown to result from a homozygous missense mutation (c.1015T>C [p.C339R]) in ZNF513, encoding a presumptive transcription factor. znf513 is expressed in the retina, especially in the outer nuclear layer, inner nuclear layer, and photoreceptors. Knockdown of znf513 in zebrafish reduces eye size, retinal thickness, and expression of rod and cone opsins and causes specific loss of photoreceptors. These effects are rescued by coinjection with wild-type (WT) but not p.C339R-znf513 mRNA. Both normal and p.C339R mutant ZNF513 proteins expressed in COS-7 cells localize to the nucleus. ChIP analysis shows that only the wild-type but not the mutant ZNF513 binds to the Pax6, Sp4, Arr3, Irbp, and photoreceptor opsin promoters. These results suggest that the ZNF513 p.C339R mutation is responsible for RP in this family and that ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance.
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakaya
authors.forename: Venkata R M
authors.initials: VR
authors.lastname: Chavali
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ma
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jiao
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sieving
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Stanislav I
authors.initials: SI
authors.lastname: Tomarev
authors.forename: Radha
authors.initials: R
authors.lastname: Ayyagari
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D002843:Chromatin; D005136:Eye Proteins; D005819:Genetic Markers; D050505:Mutant Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C552555:ZNF513 protein, human; C552556:ZNF513 protein, mouse; D029961:Zebrafish Proteins; C552557:znf513a protein, zebrafish
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