Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene () Essential for Maintenance of the Photoreceptor

Freund, Carol L.; Gregory‐Evans, Cheryl Y.; Furukawa, Takahisa; Papaioannou, Myrto; Looser, Jens; Ploder, Lynda; Bellingham, James; Ng, David; Herbrick, Jo Anne; Duncan, Alessandra M.V.; Scherer, Stephen W.; Tsui, Lap Chee; Loutradis-Anagnostou, Aphrodite; Jacobson, Samuel G.; Cepko, Constance L.; Bhattacharya, Siladitya; McInnes, Roderick R.

doi:10.1016/s0092-8674(00)80440-7

Cited by 503 publications

(346 citation statements)

References 53 publications

(29 reference statements)

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“…1 For instance, the dysfunction of genes involved in either of the phototransduction cascades, such as the CRX and NRL genes, leads to retinal dystrophy. 34,35 With the aim of detecting mutations in possible novel candidate genes in a cost-effective way, a capture panel including 88 possible candidate genes and 32 retina-abundant miRNAs was designed. Most recently, mutations in the SIX6 gene, included in our panel, were linked to an abnormal proliferation-differentiation balance and optic nerve degeneration.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

180

126

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Purpose: Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Because of extreme genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined, and there is limited information on genotype-phenotype correlations. The purpose of this study was to elucidate the mutational spectrum and genotype-phenotype correlations of IRD. Methods:We developed a targeted panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, used for exome sequencing. A total of 179 Chinese families with IRD were recruited. Results:In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel mutations (detection rate, 55.3%). Moreover, novel genotype-phenotype correlations were discovered, and phenotypic trends noted. Three cases are reported, including the identification of AHI1 as a novel candidate gene for nonsyndromic retinitis pigmentosa. Conclusion:This study revealed novel genotype-phenotype correlations, including a novel candidate gene, and identified 124 genetic defects within a cohort with IRD . The identification of novel genotype-phenotype correlations and the spectrum of mutations greatly enhance the current knowledge of IRD phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments of IRD patients.

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Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

180

126

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“…The first piece of evidence for Crx's role in development and maintenance of photoreceptors came from genetic studies performed by Freund et al (1997), who cloned the human CRX gene based on its homology in the homeodomain to another retinal homeodomain protein, Chx10. The human CRX gene maps to 19q13.3, within a cone-rod dystrophy (CORD2) locus.…”

Section: Human Genetic Studiesmentioning

confidence: 99%

“…The human CRX gene maps to 19q13.3, within a cone-rod dystrophy (CORD2) locus. Subsequent genetic screens not only identified CRX mutations in autosomal dominant cone-rod dystrophy (Freund et al, 1997), but also in autosomal dominant retinitis pigmentosa (adRP) (Sohocki et al, 1998) and Leber's congenital amaurosis (LCA) Rivolta et al, 2001b). Most CRX mutations are inherited in an autosomal dominant manner or occur de novo, particularly in LCA cases (Rivolta et al, 2001a).…”

Section: Human Genetic Studiesmentioning

confidence: 99%

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

2008

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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“…(Akagi, et al, 2004, Brown, et al, 1998, Brown, et al, 2001, Hojo, et al, 2000, Kanekar, et al, 1997, Marquardt and Gruss, 2002, Moore, et al, 2002, Morrow, et al, 1999, Yan and Wang, 1998 Several transcription factors are clearly essential for photoreceptor development, and their mutations cause retinal degenerations: NRL, CRX, Otx2, Trβ2 (thyroid hormone receptor β2), and NR2E3. (Bessant, et al, 1999, DeAngelis, et al, 2002, Freund, et al, 1997, Haider, et al, 2000, Haider, et al, 2001, Martinez-Gimeno, et al, 2001, Ng, et al, 2001, Nishida, et al, 2003, Swain, et al, 1997 However, our knowledge of the interactions of these cell-specific proteins with each other and upstream signal transduction proteins remains sparse. We do not know how this pool of cell-specific transcription factors interacts with the pool of ubiquitous proteins, which include the general transcription machinery and epigenetic regulators of chromatin/DNA structure.…”

Section: Introductionmentioning

confidence: 99%

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

Mali

Zhang

Hoerauf

et al. 2007

Experimental Eye Research

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FIZ1 (Flt-3 Interacting Zinc-finger) interacts and co-purifies with the rod-specific transcription factor NRL (Neural Retina Leucine zipper). We hypothesize that FIZ1 is part of an interface between cell-specific factors, like NRL, and more ubiquitous regulatory networks that vary the absolute expression levels of some rod-specific genes (i.e. Rhodopsin). As part of an ongoing exploration of FIZ1's role in neural retina, in vivo, we have taken the first look at FIZ1 expression in the developing mouse retina during the retinal maturation period. Using the normal C57/B6 mouse as a model, multiple approaches were used including: immunoblotting, immunohistochemistry, and quantitative real-time PCR. Functional implications of FIZ1/NRL interaction, on NRL-and CRX-mediated activation of the Rhodopsin (Rho) and cGMPphosphodiesterase β-subunit gene (PDE6B) promoters, were examined by co-transfection assays. Immunoblot analysis revealed that FIZ1 protein levels were lowest in immature mouse neural retina (P0). FIZ1 concentration increased at least ten-fold as the neural retina matured to the adult state (P21 and later). Immunohistochemical comparison of immature post-natal and mature adult retina revealed increasing FIZ1 protein in photoreceptors, the inner plexiform layer, and the ganglion cell layer. Total retinal Fiz1 mRNA content increased as the neural retina matured. The expected increase in Rho mRNA level was also monitored as a genetic marker of photoreceptor maturation. In transient co-transfection assays of CV1 cells, FIZ1 synergized with NRL to activate transcription from the Rho and PDE6B gene promoters with some differences. In the case of the Rho promoter, FIZ1 synergized when both NRL and CRX were present. With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy.Conclusions-These findings support previous evidence that FIZ1 is present in rodphotoreceptors. (Co-immunoprecipitation from nuclear-protein extracts with rod-specific NRL) FIZ1 expression increases in the neural retina during the retinal maturation period. Additionally, in vitro experiments demonstrate that FIZ1 has the potential to significantly increase the NRLmediated activation of photoreceptor-specific promoters. While CRX is not a strong activator of the PDE6B promoter, alone or with NRL, CRX decreased the synergy of NRL with FIZ1.

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Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene () Essential for Maintenance of the Photoreceptor

Cited by 503 publications

References 53 publications

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro

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