A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/2010; 87(3):400-9. DOI: 10.1016/j.ajhg.2010.08.003
Source: PubMed


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.

Download full-text


Available from: Stanislav I Tomarev, Oct 04, 2015
52 Reads
  • Source
    • "Two-point linkage analysis with markers at the RDH5 locus was performed using the FASTLINK version of MLINK from the LINKAGE Program Package, whereas maximum LOD scores were calculated using ILINK. Autosomal recessive RD was analyzed as a fully penetrant trait with an affected allele frequency of 0.001 [13] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Exome and whole-genome analyses powered by next-generation sequencing (NGS) have become invaluable tools in identifying causal mutations responsible for Mendelian disorders. Given that individual exomes contain several thousand single nucleotide variants and insertions/deletions, it remains a challenge to analyze large numbers of variants from multiple exomes to identify causal alleles associated with inherited conditions. To this end, we have developed user-friendly software that analyzes variant calls from multiple individuals to facilitate identification of causal mutations. The software, termed ÒexomeSuite,Ó filters for putative causative variants of monogenic diseases inherited in one of three forms: dominant, recessive caused by a homozygousvariant, or recessive caused by two compound heterozygous variants. In addition, exomeSuite can perform homozygosity mapping and analyze the variant data of multiple unrelated individuals. Here we demonstrate that filtering of variants with exomeSuite reduces datasets to a fraction of a percent of their original size. To the best of our knowledge this is the first freely available software developed to analyze variant data from multiple individuals that rapidly assimilates and filters large data sets based on pattern of inheritance.
    Genomics 03/2014; 103(2-3). DOI:10.1016/j.ygeno.2014.02.006 · 2.28 Impact Factor
  • Source
    • "and RP28, a 14-Mb autosomal recessive RP interval flanked by D2S1337 and D2S286 on chromosome 2p11-p15 [25,26]. The causative genes have recently been reported for both regions in September 2010, respectively ZNF513[27] for RP54 and FAM161A for RP28 [28,29]. A third gene, C2ORF71, was identified earlier this year next to ZNF513, by homozygosity mapping in two independent studies in an 8-Mb locus on chromosome 2p24.1-p23.1 and in a 6.8-Mb locus on chromosome 2p23.1-p24.1 [30,31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad) CRD. Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.
    BMC Medical Genetics 04/2011; 12(1):54. DOI:10.1186/1471-2350-12-54 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents a rule extraction method from a trained neural network (NN), which is used for keywords extraction from images. In our approach, first, a bit map image in the RGB color space is transformed into that in the L*a*b* color space. Next, it clusters image pixels using the fuzzy c-means method and domains are extracted through a labeling process. Features, such as area of obtained domains, color information, and coordinates of the center of gravity, are then calculated, which are used as input attributes to NN. NN is then trained using such features. After NN learning, rule extraction is carried out using binarized output values in the hidden layer for each keyword. The rules extracted in this paper are If-then rules, which include logical functions. The methods of generating keywords using NN and the rules are presented and their comparative experiments are performed. Finally the validity of these methods was verified by means of computer simulations.
    Fuzzy Information, 2004. Processing NAFIPS '04. IEEE Annual Meeting of the; 07/2004
Show more