The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype

Hull, Sarah; Arno, Gavin; Plagnol, Vincent; Chamney, Sarah; Russell‐Eggitt, Isabelle; Thompson, Dorothy; Ramsden, Simon; Black, Graeme C M; Robson, Anthony G.; Holder, Graham E.; Moore, Anthony T.; Webster, Andrew R.

doi:10.1167/iovs.14-14715

Cited by 64 publications

(78 citation statements)

References 54 publications

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“…CRX, and specifically Arg41 mutations, has been associated with cone-rod dystrophy, 51 macular dystrophy, or autosomal dominant RP. 52,53 The depictions of phenotype for the Arg41Trp mutation in the literature do not clearly represent a pericentral pattern of disease, although a frameshift mutation (Cys202Sfs*17) does show this pattern by OCT. 53 Two patients had mutations in RDS/PRPH2 or RHO, photoreceptor-specific genes associated with ad retinal degenerations. P24 had the Y141C RDS mutation, which has been reported to exhibit phenotypic variability, with some patients showing maculopathy only and others having widespread retinal degeneration (reviewed in Ref.…”

Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

“…For example, RDS, CRX, PROM1, and ABCA4 have all been associated with RP, macular dystrophy and cone-rod dystrophy. 53,54,61,62,69,70 RHO is associated with different patterns of disease, from early retina-wide rod loss to initially delimited altitudinal or sectoral defects. 29,71 A pericentral disease distribution has been reported in a patient with a RHO T58R mutation (Fig.…”

Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

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Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Matsui

Cideciyan

Schwartz

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Patients were screened for an annular ring scotoma ranging from 38 to 408 (n ¼ 28, ages 24-71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed.RESULTS. Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density.CONCLUSIONS. Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone-rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity.

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Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Matsui

Cideciyan

Schwartz

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…The heterozygous animal has a severe phenotype of cone-led retinal dystrophy and is a model for one form of severe early childhood onset blindness (LCA7). While most mutations in CRX result in LCA7, other phenotypes including cone-rod dystrophy, RP and macular degeneration have been described [129][130][131]. CRX mutations have been reported to account for between 0.6% and 2.35% of LCA [131][132][133][134].…”

Section: Crxmentioning

confidence: 99%

Large Animal Models of Inherited Retinal Degenerations: A Review

Winkler

Occelli

Petersen‐Jones

2020

Cells

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Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.

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“…Crx knockout mice exhibit a thinner outer segment and severely abnormal synaptic endings in the outer plexiform layer (Morrow et al, 2005). Crx mutations may lead to many diseases, such as retinitis pigmentosa (RP), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA) (Freund et al, 1997;Swain et al, 1997;Hull et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Crx Is Posttranscriptionally Regulated by Light Stimulation in Postnatal Rat Retina

Qiu

Chen

et al. 2020

Front. Cell Dev. Biol.

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Cone rod homeobox (Crx) plays a key role at the center of a regulatory network that coordinates many pathways in the retina. Its abnormal expression induces retinal disorders. However, the underlying regulatory mechanism of Crx expression is not well defined. Here, we present data that show that the levels of Crx mRNA were inconsistent with that of Crx protein in primary retinal neurocytes cultured in light conditions. Crx protein levels were significantly higher (2.56-fold) in cells cultured in the dark than in cells cultured in light, whereas Crx mRNA was not changed in either type of cell. Moreover, the expression of Crx protein showed a significant light intensity-dependent decrease. Consistently, Crx downstream genes rhodopsin and arrestin also decreased in retinal neurocytes upon light exposure. Furthermore, Crx promoter activity assay performed in primary retinal neurocytes further indicated that light exposure and darkness did not affect its inducibility. In addition, the inconsistency between Crx mRNA and protein expression after light exposure was not observed in 661w cells transfected with plasmid pcDNA3.1-Crx, suggesting that the inconsistency between Crx mRNA and protein induced by light was specific to the endogenous Crx. More importantly, this observation was confirmed in vivo in postnatal day 15 (P15) retinas but not in adult retinas, further implicating that the posttranscriptional regulation mechanism may be involved in Crx expression in the developing retina. Therefore, our study sheds light on the mechanism of Crx expression in postnatal rat retina.

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The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype

Abstract: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.

Cited by 64 publications

References 54 publications

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Large Animal Models of Inherited Retinal Degenerations: A Review

Crx Is Posttranscriptionally Regulated by Light Stimulation in Postnatal Rat Retina

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