A Range of Clinical Phenotypes Associated with Mutations in CRX, a Photoreceptor Transcription-Factor Gene

Sohocki, Melanie M.; Sullivan, Lori S.; Mintz-Hittner, Helen A.; Birch, David G.; Heckenlively, John R.; Freund, Carol L.; McInnes, Roderick R.; Daiger, Stephen P.

doi:10.1086/302101

Cited by 243 publications

(166 citation statements)

References 13 publications

Supporting

Mentioning

160

Contrasting

Order By: Relevance

“…RP is a family of inherited retinal diseases characterized by degeneration of rod photoreceptor cells leading to night blindness, visual field restriction, and eventually complete loss of visual function. Most genes associated with autosomal dominant forms of RP are expressed specifically in rod photoreceptors, including genes associated with phototransduction (RHO, GUCA1B) (33,34), photoreceptor-specific transcription factors (CRX, NRL) (35,36), or structural characteristics specific to photoreceptors (RDS, RP1) (37)(38)(39)(40). Other autosomal dominant RP genes are expressed in heterogeneous tissues including the retina and/or the retinal pigment epithelium, such as pre-mRNA splicing factors PRPF3, PRPF8, and PRPF31 (41-43) and the transmembrane protein SEMA4A (44).…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response

Ogilvie¹,

Ohlemiller

Shah

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Members of the carbonic anhydrase (CA) family play an important role in the regulation of pH, CO 2 , ion, and water transport. CA IV and CA XIV are membrane-bound isozymes expressed in the eye. CA IV immunostaining is limited to the choriocapillaris overlying the retina, whereas CA XIV is expressed within the retina in Müller glial cells and retinal pigment epithelium. Here, we have characterized the physiological and morphological phenotype of the CA IV-null, CA XIV-null, and CA IV/CA XIV-double-null mouse retinas. Flash electroretinograms performed at 2, 7, and 10 months of age showed that the rod/cone a-wave, b-wave, and cone b-wave were significantly reduced (26–45%) in the CA XIV-null mice compared with wild-type littermates. Reductions in the dark-adapted response were not progressive between 2 and 10 months, and no differences in retinal morphology were observed between wild-type and CA XIV-null mice. Müller cells and rod bipolar cells had a normal appearance. Retinas of CA IV-null mice showed no functional or morphological differences compared with normal littermates. However, CA IV/CA XIV double mutants showed a greater deficit in light response than the CA XIV-null retina. Our results indicate that CA XIV, which regulates extracellular pH and pCO 2 , plays an important part in producing a normal retinal light response. A larger functional deficit in the CA IV/CA XIV double mutants suggests that CA IV can also contribute to pH regulation, at least in the absence of CA XIV.

show abstract

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response

Ogilvie¹,

Ohlemiller

Shah

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…This observation raises the question to know whether non-truncating mutations of this gene could be involved in autosomal recessive retinal dystrophies less severe than LCA. Indeed, LCA-associated mutations are commonly deleterious mutations and mutations in several LCA genes can be responsible for autosomal recessive retinal dystrophies (retinitis pigmentosa or cone-rod dystrophies) [Gu et al, 1997;Freund et al, 1997;Banerjee et al, 1998;Sohocki et al, 1998;Lewis et al, 1999;den Hollander 1999;Lorenz et al, 2000;den Hollander et al, 2001;Sohocki et al, 2001;Thompson et al, 2001Thompson et al, , 2002Hameed et al, 2003;den Hollander et al, 2004;Janecke et al, 2004;Perrault et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

et al. 2007

View full text Add to dashboard Cite

Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophy responsible for blindness or severe visual impairment at birth or within the first months of life. Up to date, ten LCA genes have been identified. Three of them account for ca. 43% of families and are responsible for a congenital severe stationary cone-rod dystrophy (Type I, 60 % of LCA) while the seven remaining genes account for 32% of patients and are responsible for a progressive yet severe rod-cone dystrophy (Type II, 40 % of LCA ). Recently, mutations in LCA5, encoding the ciliary protein lebercilin, were reported to be a rare cause of leber congenital amaurosis. The purpose of this study was to evaluate the involvement of this novel gene and to look for genotype-phenotype correlations. Here we report the identification of three novel LCA5 mutations (3/3 homozygous) in three families confirming the modest implication of this gene in our series (3/179; 1.7%). Besides, we suggest that the phenotype of these patients affected with a particularly severe form of LCA type II may represent a continuum with LCA type I.

show abstract

“…However, the role of Crx in the maintenance of retina-specific gene expression in the mature retina is less clear. Crx mutations are often associated with degenerative disease with variable onset (55)(56)(57)(58)(59). However, it is also well established that over and underexpression of rhodopsin can cause photoreceptor degeneration (13,14,16).…”

Section: Discussionmentioning

confidence: 99%

Conserved Transcriptional Activators of the Xenopus Rhodopsin Gene

Whitaker

Knox

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Vertebrate rhodopsin promoters exhibit striking sequence identities proximal to the initiation site, suggesting that conserved transcription factors regulate rhodopsin expression in these animals. We identify and characterize two transcriptional activators of the Xenopus rhodopsin gene: homologs of the mammalian Crx and Nrl transcription factors, XOtx5 and XL-Nrl (originally named XL-maf), respectively. XOtx5 stimulated transcription ϳ10-fold in human 293 cells co-transfected with a plasmid containing the rhodopsin promoter (؊508 to ؉41) upstream of luciferase, similar to the ϳ6-fold stimulation with human Crx. XL-Nrl stimulated transcription ϳ27-fold in mammalian 293 cells co-transfected with the rhodopsin luciferase reporter, slightly more than the ϳ17-fold stimulation with Nrl. Together, the Xenopus transcription factors synergistically activated the rhodopsin promoter (ϳ140-fold), as well as in combination with mammalian homologs. Deletion of the Nrl-response element, TGCTGA, eliminated the synergistic activation by both mammalian and Xenopus transcription factors. Deletion of the conserved ATTA sequences (Ret-1 or BAT-1), binding sites for Crx, did not significantly decrease activation by Crx/XOtx5. However, there was increased activation by Nrl/XL-Nrl and an increased synergy when the Ret-1 site was disrupted. These results illustrate conservation of mechanisms of retinal gene expression among vertebrates. In transgenic tadpoles, XOtx5 and XL-Nrl directed premature and ectopic expression from the Xenopus rhodopsin promoter-GFP transgene. Furthermore, activation of the endogenous rhodopsin gene was also observed in some animals, showing that XOtx5 and XL-Nrl can activate the promoter in native chromatin environment.Photoreceptors are highly specialized cells with complex structures that permit efficient light absorption, high signal transduction amplification, rapid kinetics, and adaptation over a range of light intensities (1). Phototransduction requires the coordinated expression of many genes, including the visual pigments that absorb light, enzymes involved in the cGMP cascade, ion channels plus multiple regulatory and structural proteins. It has been estimated using serial analysis of gene expression that ϳ4% of the genes expressed in the retina encode phototransduction proteins (2). Many of these genes are quite conserved in vertebrates. Moreover, programs of eye development share many conserved features in the animal kingdom (3, 4). Even in such distantly related species as Drosophila and humans, similar transcription factors are involved in development and expression of retina-specific genes (5, 6), although the evolutionary significance is not yet settled (5, 7, 8). Often, proteins involved in growth and differentiation of the eye from one species can substitute for homologs in distantly related species (4, 7). This conservation also extends to the cis-acting elements in proximal promoters of retinal genes. Promoters have exhibited at least partial functionality between mammals and lower vertebrate...

show abstract

A Range of Clinical Phenotypes Associated with Mutations in CRX, a Photoreceptor Transcription-Factor Gene

Cited by 243 publications

References 13 publications

Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response

Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

Conserved Transcriptional Activators of the Xenopus Rhodopsin Gene

Contact Info

Product

Resources

About