ZFIN ID: ZDB-PUB-100830-5
A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa
Li, L., Nakaya, N., Chavali, V.R., Ma, Z., Jiao, X., Sieving, P.A., Riazuddin, S., Tomarev, S.I., Ayyagari, R., Riazuddin, S.A., and Hejtmancik, J.F.
Date: 2010
Source: American journal of human genetics   87(3): 400-409 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Chromatin/metabolism
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Eye Proteins/chemistry
  • Eye Proteins/genetics*
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, Recessive/genetics*
  • Genetic Markers
  • Humans
  • Lod Score
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins/metabolism
  • Mutation/genetics*
  • Pedigree
  • Photoreceptor Cells, Vertebrate/metabolism*
  • Photoreceptor Cells, Vertebrate/pathology
  • Protein Binding
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Retinal Cone Photoreceptor Cells/pathology
  • Retinal Rod Photoreceptor Cells/pathology
  • Retinitis Pigmentosa/genetics*
  • Transcription Factors/chemistry
  • Transcription Factors/genetics*
  • Zebrafish/embryology
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
PubMed: 20797688 Full text @ Am. J. Hum. Genet.
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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.
ADDITIONAL INFORMATION