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Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone–rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient's symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene. [ABSTRACT FROM AUTHOR]

Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone–rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient’s symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene.

Purpose: Cone-rod dystrophy (CRD) is an inherited retinal dystrophy that is transmitted via different modes of inheritance. Mutations in more than 30 genes have been identified to cause the disease. We aimed to investigate the genetic agents of two unrelated cone-rod dystrophy affected Iranian families with autosomal recessive inheritance patterns. Methods: Whole-exome sequencing (WES) was performed for identification of the disease-causing mutations in the probands of both families. The candidate mutations were further confirmed by Sanger sequencing. Samples from five available members of each family were then sequenced for the mutations present in the probands. Comprehensive ocular examinations for all members of the families carrying the mutations were completed by ophthalmologists. Results: We identified a novel premature stop codon c.310C>T in CRX gene in heterozygote form in two symptomatic and two non-symptomatic members of one family (family-A), and a known CRX mutation c.122G>A in homozygote form in another (family B). c.122G>A has been reported to cause late-onset autosomal dominant form of the disease in previous studies. However, the middle-aged heterozygous carriers of the mutation in this family showed normal phenotype. Conclusion: The CRX gene has been previously linked to the autosomal dominant form of cone-rod dystrophy. We report incomplete penetrance of CRX gene for autosomal dominant form of the disease. Incomplete penetrance of the mutations may be partly caused by the influence of other genes in the complex genetic network underlying retinal regulation. [ABSTRACT FROM AUTHOR]

AIM: To identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD). METHODS: A southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members. RESULTS: The results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation. CONCLUSION: All modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.

Purpose: To present the clinical and electrophysiological findings in four members of a family with Best vitelliform macular dystrophy (BVMD) and angle-closure glaucoma (ACG). Methods: Four members of a family with BVMD were examined clinically, including visual acuity, slit-lamp examination, biomicroscopy, Goldmann applanation tonometry and gonioscopy. Measurements of the anterior chamber depth and axial length, visual field, optical coherence tomography, full-field electroretinography, multifocal electroretinography and electrooculography were performed. In addition molecular genetic analysis of the bestrophin-1 gene ( BEST1), the microphthalmia-associated transcription factor gene ( MITF) and the cone-rod homeobox gene ( CRX) were performed. Results: Four family members with the c.253T>C p.Y85H mutation in the BEST1 gene and BVMD in different stages also exhibited anterior segment abnormalities such as shallow anterior chambers (two cases), and reduced axial lengths in all cases. Microphthalmos (axial length ≤ 20mm) was found in the index patient and in her son. Hyperopia was found in all four examined patients. Closed angles/narrow angles were observed in patients with microphthalmos. The index patient developed ACG at the age of 12 years. Her son inherited microphthalmos, severe hyperopia, and narrow angles. He is at risk of developing ACG. No pathogenic mutation of the MITF or the CRX genes was detected in the index patient. Conclusions: BVMD could be associated with anterior segment abnormalities such as shallow anterior chambers, closed/narrow anterior chamber angles and ACG. Ophthalmologists should be aware of the association between ACG and BVMD. Examination of the anterior segment, gonioscopy and intraocular pressure control are recommended in patients with BVMD. [ABSTRACT FROM AUTHOR]

The CRX gene encoding the cone-rod homeobox protein is a specific photoreceptor transcription factor crucial for retinal function. Persons temporarily residing in the Arctic zone during the polar summer may suffer from disturbances associated with extremely high ambient illumination. These environmental changes are mediated by retinal photoreceptors; therefore, it is important to study the expression of retinal genes in order to assess individual capacities of sensory adaptation to polar day conditions., Purpose: To reveal the dynamics of CRX expression level in humans after a prolonged temporary exposure to polar day conditions., Material and Methods: The study included 6 pilots (males from 39 to 69 y.o.) who participated in the Arctic World Oceanic International Flight Sever Vash (West to East, from 62°N 74°E to 72°N 114°E). Samples of peripheral blood for RNA isolation were collected at the start and at the end of the flight. The level of mRNA in the samples was evaluated based on the data of quantitative real-time PCR of the CRX gene, as well as the b2M and TBP housekeeping genes (reference)., Results: Expression of the CRX gene in the studied group ( p <0.01) was revealed; the total average level of mRNA was about 3 times higher prior to, and approximately 7 times higher after normalization to the b2M gene. Five pilots had increased expression of the CRX gene within the range of -1.53 to -3.07 (Z-score of <0 before the flight and >0 after the flight). In one pilot, the level of CRX expression was higher at the start, but it reduced by the end of the circumnavigation flight., Conclusions: The results confirm the hypothesis that the CRX gene is expressed after a prolonged temporary exposure to polar day conditions. It was also revealed that during rapid adaptation, equal changes in the illumination of retinal photoreceptors lead to different individual dynamics of CRX expression.

Objective: To investigate whether exogenous CRX gene would be able to induce Müller cells-derived progenitors to differentiate into photoreceptors. Methods: Experimental study. Müller cells-derived progenitors resulted from primary Müller cells isolated from KunMing mice(5-7 days old) and cultured in free-serum media. Markers of Müller cells(glutamine synthetase, GS and Vimentin) and stem cells (Nestin and Sox2) were analysed by immnocytochemical assays. The secondary passage progenitors were divided into three groups: (1)the control group; (2)the empty vector group was transfected with lentivirus GFP; (3)the treated group was transfected with lentivirus GFP-CRX. After differentiation for 7 days, 7 days after differentiation, the expression of markers of photoreceptors were analyzed by q-PCR and Western blot assay. Results: There were 96.03%±1.21% of Müllerz cells cultured in vitro were immunoreactive to both GS and Vimentin. The dedifferentiation cells expressed Nestin and Sox2. After 7 days of induction, Exogenous CRX induced Müller cell-derived progenitors to differentiate into rod-like cells showed appearance like neuron morphology. q-PCR demonstrated that mRNAs of CRX and Rhodopsin were upregulated greatly. CRX mRNA were 9 times ( P< 0.05) and Rhodopsin mRNA were 20 times ( P< 0.05). The difference between the control group and the empty vector group was not statistically significant. Western blot showed that the expression of CRX was upregulated significantly, and was 2.7 times( P< 0.05). But expression of Rhodopsin was weak and was nearly not detected in the control group and empty vector group. The expression of S-opsin was not detected. Conclusion: CRX gene could induce the differentiation of Müller cell-derived progenitor into rod photoreceptors, indicating a new avenue to study müller cells as endogenous seed cells for retinal photoreceptor. (Chin J Ophthalmol, 2018, 54: 923-928) .