| 1. |
- Abdalla-Elsayed, Maram E.A., et al.
(författare)
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Heterozygous mutation in OTX2 associated with early-onset retinal dystrophy with atypical maculopathy
- 2017
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Ingår i: Molecular Vision. - 1090-0535. ; 23, s. 778-784
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Heterozygous mutations in OTX2 have been associated with a range of ocular and pituitary abnormalities. We report a novel heterozygous deletion in OTX2 underlying early-onset retinal dystrophy with atypical maculopathy. Methods: Clinical examination included electroretinography and multimodal retinal imaging. Molecular genetic testing was composed of next-generation sequencing of a panel of retinal dystrophy genes. Results: A now 17-year-old boy presented 12 years earlier with a history of progressively poor vision since birth, nyctalopia, and early-onset retinal dystrophy with atypical maculopathy. He also had bilateral microphthalmos and a slim prepubertal appearance; growth hormone levels were within normal ranges. Next-generation sequencing of a retinal dystrophy gene panel revealed a heterozygous deletion c.485delC (p.Pro162G.Infs*24) in exon 5 of OTX2. Conclusions: This second report of maculopathy associated with a heterozygous mutation in OTX2 confirms that mutations in OTX2 should be considered in the differential diagnosis of atypical hereditary maculopathy, with or without rod-cone dystrophy.
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| 2. |
- Abdulridha-Aboud, Wissam, et al.
(författare)
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Characterization of macular structure and function in two swedish families with genetically identified autosomal dominant retinitis pigmentosa
- 2016
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Ingår i: Molecular Vision. - 1090-0535. ; 22, s. 362-373
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods: Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results: The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions: These two families demonstrate the extreme inter-and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype.
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| 3. |
- Acar, C, et al.
(författare)
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Mutation screening of patients with Leber congenital amaurosis or the enhanced S-cone syndrome reveals a lack of sequence variations in the NRL gene
- 2003
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Ingår i: Molecular Vision. - 1090-0535. ; 9:3-4, s. 14-17
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To determine if mutations in the retinal transcription factor gene NRL are associated with retinopathies other than autosomal dominant retinitis pigmentosa (adRP). Methods: Genomic DNA was isolated from blood samples obtained from 50 patients with Leber Congenital Amaurosis (LCA), 17 patients with the Enhanced S-Cone Syndrome (ESCS), and a patient with an atypical retinal degeneration that causes photoreceptor rosettes with blue cone opsin. The 5' upstream region (putative promoter), untranslated exon 1, coding exons 2 and 3, and exon-intron boundaries of the NRL gene were analyzed by direct sequencing of the PCR-amplified products. Results: Complete sequencing of the NRL gene in DNA samples from this cohort of patients revealed only one nucleotide change. The C->G transversion at nucleotide 711 of NRL exon 3 was detected in one LCA patient; however, this change did not alter the amino acid (L237L). Conclusions: No potential disease causing mutation was identified in the NRL gene in patients with LCA, ESCS, or the atypical retinal degeneration. Together with previous studies, our results demonstrate that mutations in the NRL gene are not a major cause of retinopathy. To date, only missense changes have been reported in adRP patients, and sequence variations are rare. It is possible that the loss of NRL function in humans is associated with a more complex clinical phenotype due to its expression in pineal gland in addition to rod photoreceptors.
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| 4. |
- Agudo, Marta, et al.
(författare)
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Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush
- 2008
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Ingår i: Molecular Vision. - 1090-0535. ; 14, s. 1050-1063
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT).METHODS:RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naïve and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.).RESULTS:Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naïve and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling.CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.
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| 5. |
- Al-Hujaili, Haneen, et al.
(författare)
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Long-term follow-up of retinal function and structure in trpm1-associated complete congenital stationary night blindness
- 2019
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Ingår i: Molecular Vision. - 1090-0535. ; 25, s. 851-858
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: TRPM1-associated congenital stationary night blindness (CSNB) is characterized by nystagmus and high myopia. We assessed retinal function and structure over long-term follow-up up to 10 years in two siblings from a family with the homozygous deletion c.2394delC in exon 18 that we previously identified. In addition, we describe retinal function and structure in two other siblings with the novel homozygous c.1394T>A (p.Met465Lys) missense mutation. Methods: Clinical examination included full-field electroretinography, axial length measurements, and multimodal retinal imaging. Molecular genetic tests included next-generation sequencing and Sanger sequencing. Results: All patients had non-recordable rod responses and electronegative configuration of the rod-cone responses at presentation. There was a median of 26% reduction in the dark-and light-adapted electroretinographic (ERG) amplitudes over 4 years. Myopia progressed rapidly in childhood but showed only a mild progression after the teenage years. Visual acuities were stable over time, and there was no sign of progressive retinal thinning. All patients had axial myopia. A novel homozygous c.1394T>A (p.Met465Lys) missense mutation in TRPM1 was identified in two siblings. Conclusions: Further prospective study in larger samples is needed to establish whether there is progressive retinal degeneration in TRPM1-associated CSNB. The associated myopia was found to be mainly axial, which has not been described previously. The mechanism of myopia development in this condition remains incompletely understood; however, it may be related to altered retinal dopamine signaling and amacrine cell dysfunction.
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| 6. |
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| 7. |
- Behndig, Anders
(författare)
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Corneal endothelial integrity in aging mice lacking superoxide dismutase-1 and/or superoxide dismutase-3.
- 2008
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Ingår i: Molecular Vision. - 1090-0535. ; 14, s. 2025-30
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the age-induced changes in corneal endothelial morphology in mice lacking the cytosolic copper-zinc superoxide dismutase (SOD-1), the interstitial extracellular superoxide dismutase (SOD-3), or both of these SOD isoenzymes. METHODS: The central corneal endothelial morphologies of old C57BL-6J wild type (n=19), SOD-1 null (n=16), SOD-3 null (n=15), and SOD1/3 null (n=11) mice were evaluated using alizarin red staining and light microscope photographs. For comparison, young endothelia from the same genotypes were evaluated similarly. The levels of corneal reactive oxygen species and nitrogen species in all four genotypes were quantified using fluorimetry with 2',7'-dichlorodihydrofluorescein diacetate and OxyBURST. RESULTS: In accordance with our previous findings, the mean corneal endothelial cell area was larger in the SOD-3 null genotype than in the wild type mice. The SOD-1/3 null genotype had similar cell sizes as the SOD-3 null mice but had a more irregular morphology at an older age. Apparently, these irregularities develop with time as they are not seen in young animals. The SOD-1 null mice did not differ from the wild type mice in corneal endothelial morphology. Elevated levels of reactive oxygen species were seen in SOD-1 null and SOD-3 null corneas, and elevated superoxide levels were seen in all three knockout genotypes. CONCLUSIONS: The increased spontaneous age-related enlargement of corneal endothelial cells seen in the absence of SOD-3 is associated with a more irregular cell pattern when combined with a lack of SOD-1. This indicates more cellular movements and ongoing repair in the SOD-1/3 null genotype and possibly a more vulnerable corneal endothelium. SOD-3 and SOD-1 appear to have functions in preserving corneal endothelial integrity in aging.
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| 8. |
- Blixt, Maria, 1984-, et al.
(författare)
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A regulatory sequence from the retinoid X receptor gamma gene directs expression to horizontal cells and photoreceptors in the embryonic chicken retina
- 2016
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Ingår i: Molecular Vision. - 1090-0535. ; 22, s. 1405-1420
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Combining techniques of episomal vector gene-specific Cre expression and genomic integration using the piggyBac transposon system enables studies of gene expression-specific cell lineage tracing in the chicken retina. In this work, we aimed to target the retinal horizontal cell progenitors. METHODS: A 208 bp gene regulatory sequence from the chicken retinoid X receptor gammagene (RXRgamma208) was used to drive Cre expression. RXRgamma is expressed in progenitors and photoreceptors during development. The vector was combined with a piggyBac "donor" vector containing a floxed STOP sequence followed by enhanced green fluorescent protein (EGFP), as well as a piggyBac helper vector for efficient integration into the host cell genome. The vectors were introduced into the embryonic chicken retina with in ovo electroporation. Tissue electroporation targets specific developmental time points and in specific structures. RESULTS: Cells that drove Cre expression from the regulatory RXRgamma208 sequence excised the floxed STOP-sequence and expressed GFP. The approach generated a stable lineage with robust expression of GFP in retinal cells that have activated transcription from the RXRgamma208 sequence. Furthermore, GFP was expressed in cells that express horizontal or photoreceptor markers when electroporation was performed between developmental stages 22 and 28. Electroporation of a stage 12 optic cup gave multiple cell types in accordance with RXRgamma gene expression in the early retina. CONCLUSIONS: In this study, we describe an easy, cost-effective, and time-efficient method for testing regulatory sequences in general. More specifically, our results open up the possibility for further studies of the RXRgamma-gene regulatory network governing the formation of photoreceptor and horizontal cells. In addition, the method presents approaches to target the expression of effector genes, such as regulators of cell fate or cell cycle progression, to these cells and their progenitor.
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