CRX variants in cone–rod dystrophy and mutation overview

Huang, Li; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Wang, Panfeng; Guo, Xiangming; Zhang, Qingjiong

doi:10.1016/j.bbrc.2012.08.110

Cited by 52 publications

(54 citation statements)

References 37 publications

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“…Scale bar: 40 μm. (B) Methacrylate sections followed by H&E staining of retinas from 5-week-, 10-week-, and 9-month-old Crx +/+ , Crx Rip of missense and truncation mutations in the CRX homeodomain are associated with cone-rod dystrophy and alter its DNA binding properties or transcriptional synergy with NRL (34,35), thereby influencing gene expression and photoreceptor maturation. In contrast, many human CRX frameshift mutations identified downstream of the homeodomain result in dominant and more severe LCA phenotypes.…”

Section: Figurementioning

confidence: 99%

“…The Crx Rip mutation (CRX G255fs refers to the corresponding change in humans) is in a conserved domain of CRX, in close proximity of several similar 1-bp deletion mutations associated with dominant LCA in humans (35). We therefore selected 2 human mutations -CRX L237fs and CRX P263fs ( Figure 4A) -to test their effect on photoreceptor development in mouse retina.…”

Section: Identification Of a New Mouse Mutant With Congenital Blindnementioning

confidence: 99%

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OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

106

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Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx Rip ). We determined that Crx Rip is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the Crx Rip phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in Crx Rip retinas. Expression of NRL partially restored rod development in Crx Rip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in Crx Rip mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.

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Section: Figurementioning

confidence: 99%

Section: Identification Of a New Mouse Mutant With Congenital Blindnementioning

confidence: 99%

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

106

View full text Add to dashboard Cite

show abstract

“…CRX variation types as well as their localization within the gene are not associated with phenotypic differences (CORD vs. LCA vs. RP), indicating a lack of genotype -phenotype correlation [8].…”

Section: Introductionmentioning

confidence: 91%

“…Pathogenic variations in the CRX gene have been reported in 2.35% of LCA, in 4.76% of CORD and in 0.80% of Retinitis Pigmentosa (RP) cases [8]. CRX variation types as well as their localization within the gene are not associated with phenotypic differences (CORD vs. LCA vs. RP), indicating a lack of genotype -phenotype correlation [8].…”

Section: Introductionmentioning

confidence: 99%

Multimodal Imaging in Autosomal Dominant Cone-Rod Dystrophy Caused by Novel <b><i>CRX</i></b> Variant

et al. 2018

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Aim: To characterize by multimodal approach the phenotype of patients from a 3 generations pedigree, affected by autosomal dominant cone-rod dystrophy (CRD), found to carry a novel pathogenic variant in the cone-rod homeobox-containing (CRX) gene. Methods: Examination of the adult patients included the following tests: visual acuity, multicolour imaging, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and OCT angiography (OCT-A) recordings. In a 2.5-year-old child, cycloplegic refraction, fundoscopy, ocular motility evaluation and electrophysiological exams were performed. Next Generation Sequencing of patients’ DNA has been carried out. Results: A novel CRX pathogenic variant has been identified in our patients. The 2.5-year-old child in the third generation was found to have inherited the variant, with no clinical signs of the condition, but electroretinographic abnormalities in the scotopic component. In the adult patients, diffuse atrophy of the retinal pigment epithelium/photoreceptor complex in the macular region was evident at the OCT and FAF, while OCT-A showed choriocapillaris density reduction. Conclusions: Multimodal study allowed the characterization of a peculiar form of CRD. The novel pathogenic variant seems to have a different effect on the phenotype if compared with a previously described similar one, giving an insight into the pathogenic mechanism of CRX-related retinal dystrophies and offering valuable information that could lead to the development of possible future therapies.

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“…To the best of our knowledge, 15 different mutations have been detected in the CNNM4 gene around the world and different mutations show variable interfamilial and intrafamilial expression. 6,[19][20][21][22] Types of mutations occurring in Jalili syndrome address a clinical heterogeneity and suggest loss of function as the underlying mechanism. 7 Here, we report variable expressions of cone-rod retinal dystrophy in terms of age of onset, severity in visual impairment and progression, in four patients of our family.…”

Section: Patientmentioning

confidence: 99%

A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome

Rahimi-Aliabadi

Daftarian

Ahmadieh

et al. 2016

Eye

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Purpose Jalili syndrome is an autosomal recessive disorder characterized by simultaneous appearance of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI). Mutations in CNNM4 gene have been identified as the underlying cause of the syndrome. In this study, we investigated a large affected family to identify the causative mutation. Patients and Methods A seven-generation family with 24 members affected with Jalili syndrome were enrolled in the study. Comprehensive ophthalmologic and dental examinations were performed on them. The entire coding region of CNNM4 gene was sequenced for detection of potential mutations. Results Ocular examinations showed nystagmus and photophobia along with early onset visual impairment. Fundoscopic exams revealed a spectrum of macular dystrophies in different family members, from macular coloboma and advanced form of beaten bronze macular dystrophy (bull's eye) to milder form of macular thinning along with a range of pigmentary changes and vascular attenuation in the posterior pole and periphery. Scotopic and photopic electroretinographic responses (ERGs) were extinguished or significantly depressed. Mutation analysis revealed a novel mutation (c.1091delG) in homozygous form in the patients and as a heterozygous form in the normal carrier subjects. Conclusion We identified a novel homozygous deleterious mutation in CNNM4 gene which causes Jalili syndrome.

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CRX variants in cone–rod dystrophy and mutation overview

Cited by 52 publications

References 37 publications

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Multimodal Imaging in Autosomal Dominant Cone-Rod Dystrophy Caused by Novel <b><i>CRX</i></b> Variant

A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome

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