164 research outputs found
Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy
No full textPURPOSE:
This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement.
DESIGN:
Case series.
PARTICIPANTS:
Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders.
METHODS:
Genome-wide linkage analysis and exome sequencing were performed in 1 large family with 5 affected individuals. In addition, exome sequencing was performed in the proband of a second family. Subsequent analysis of the identified mutations in 244 patients was performed by Sanger sequencing or restriction enzyme digestion. The medical history of individuals carrying the MFSD8 variants was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), multifocal ERG (mfERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence, and fundus photography.
MAIN OUTCOME MEASURES:
MFSD8 variants, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, mfERG, fundus autofluorescence, and OCT findings.
RESULTS:
Compound heterozygous variants in MFSD8, a gene encoding a lysosomal transmembrane protein, were identified in 2 families with macular dystrophy with a normal or subnormal ERG, but reduced mfERG. In both families, a heterozygous missense variant p.Glu336Gln was identified, which was predicted to have a mild effect on the protein. In the first family, a protein-truncating variant (p.Glu381*) was identified on the other allele, and in the second family, a variant (c.1102G>C) was identified that results in a splicing defect leading to skipping of exon 11 (p.Lys333Lysfs*3). The p.Glu336Gln allele was found to be significantly enriched in patients with maculopathies and cone disorders (6/488) compared with ethnically matched controls (35/18 682; P < 0.0001), suggesting that it may act as a genetic modifier.
CONCLUSIONS:
In this study, we identified variants in MFSD8 as a novel cause of nonsyndromic autosomal recessive macular dystrophy with central cone involvement. Affected individuals showed no neurologic features typical for variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a severe and devastating multisystem lysosomal storage disease previously associated with mutations in MFSD8. We propose a genotype-phenotype model in which a combination of a severe and a mild variant cause nonsyndromic macular dystrophy with central cone involvement, and 2 severe mutations cause vLINCL
Mutation screening of retinal dystrophy patients by targeted capture from tagged pooled DNAs and next generation sequencing.
No full textPurpose: Retinal dystrophies are genetically heterogeneous, resulting from mutations in over 200 genes. Prior to the development of massively parallel sequencing, comprehensive genetic screening was unobtainable for most patients. Identifying the causative genetic mutation facilitates genetic counselling, carrier testing and prenatal/pre-implantation diagnosis, and often leads to a clearer prognosis. In addition, in a proportion of cases, when the mutation is known treatment can be optimised and patients are eligible for enrolment into clinical trials for gene-specific therapies. Methods: Patient genomic DNA was sheared, tagged and pooled in batches of four samples, prior to targeted capture and next generation sequencing. The enrichment reagent was designed against genes listed on the RetNet database (July 2010). Sequence data were aligned to the human genome and variants were filtered to identify potential pathogenic mutations. These were confirmed by Sanger sequencing. Results: Molecular analysis of 20 DNAs from retinal dystrophy patients identified likely pathogenic mutations in 12 cases, many of them known and/or confirmed by segregation. These included previously described mutations in ABCA4 (c.6088C>T,p.R2030*; c.5882G>A,p.G1961E), BBS2 (c.1895G>C,p.R632P), GUCY2D (c.2512C>T,p.R838C), PROM1 (c.1117C>T,p.R373C), RDH12 (c.601T>C,p.C201R; c.506G>A,p.R169Q), RPGRIP1 (c.3565C>T,p.R1189*) and SPATA7 (c.253C>T,p.R85*) and new mutations in ABCA4 (c.3328+1G>C), CRB1 (c.2832_2842+23del), RP2 (c.884-1G>T) and USH2A (c.12874A>G,p.N4292D). Conclusions: Tagging and pooling DNA prior to targeted capture of known retinal dystrophy genes identified mutations in 60% of cases. This relatively high success rate may reflect enrichment for consanguineous cases in the local Yorkshire population, and the use of multiplex families. Nevertheless this is a promising high throughput approach to retinal dystrophy diagnostics
Comprehensive analysis of copy number variation of genes at chromosome 1 and 10 Loci associated with late age related macular degeneration
No full textCopy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored. We analyzed the two major AMD risk-associated regions on chromosome 1q32 and 10q26 for CNVs using Multiplex Ligation-dependant Probe Amplification. The analysis targeted nine genes in these two key regions, including the Complement Factor H (CFH) gene, the 5 CFH-related (CFHR) genes representing a known copy number "hotspot", the F13B gene as well as the ARMS2 and HTRA1 genes in 387 cases of late AMD and 327 controls. No copy number variation was detected at the ARMS2 and HTRA1 genes in the chromosome 10 region, nor for the CFH and F13B genes at the chromosome 1 region. However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38 × 10(-12)) OR = 0.31, CI-0.95 (0.23-0.44), for both neovascular disease (nAMD) (p = 8.3 × 10(-9)) OR = 0.36 CI-0.95 (0.25-0.52) and geographic atrophy (GA) (p = 1.5 × 10(-6)) OR = 0.36 CI-0.95 (0.25-0.52) compared to controls. In addition, a significant association with deletion of CFHR1-4 was identified only in patients who presented with bilateral GA (p = 0.02) (OR = 7.6 CI-0.95 1.38-41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease
Alteration of retinal layers in healthy subjects over 60 years of age until nonagenarians
No full textLebriz Altay,1 Cheryl Jahn,1 Mücella Arikan Yorgun,1 Albert Caramoy,1 Tina Schick,1 Carel B Hoyng,2 Anneke I den Hollander,2 Sascha Fauser1 1Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 2Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Purpose: To assess alterations of retinal layers in healthy subjects over 60 years old. Methods: Retinal layers of 160 healthy subjects (aged 60–100 years) without any retinal pathology were imaged using spectral domain optical coherence tomography. Mean thickness of retinal nerve fiber layer, ganglion cell/inner plexiform layer (GCLIPL), inner nuclear layer, outer plexiform layer/outer nuclear layer, photoreceptor complex (PR) and retinal thickness (RT) were measured in a 3.45 mm grid. Correlations between age and layers were estimated and linear regression equations were calculated. Different age-groups (60–69, 70–79, 80–89 years and nonagenarians, each group with 40 participants) were compared. Results: Significant age-thickness correlations were observed for GCLIPL (P<0.001, r=-0.394), PR (P<0.001, r=-0.370) and RT (P<0.001, r=-0.290). A comparison between age groups 60–69 years and nonagenarians showed no significant thickness alteration of retinal nerve fiber layer (21.80±2.18 µm vs 22.82±2.97 µm, P=0.163), inner nuclear layer (37.23±3.02 µm vs 36.01±3.24 µm, P=0.07) and outer plexiform layer/outer nuclear layer (104.95±6.56 µm vs 104.23±7.59 µm, P=0.567), while GCLIPL (83.35±7.35 µm vs 74.38±9.09 µm), PR (83.03±3.31 µm vs 79.34±2.09 µm) and RT (330.64±12.63 µm vs 316.83±18.35 µm) showed a significant decrease (P<0.001 for all). Conclusion: Our study provides normative data of alterations of retinal layers for persons aged 60 years to nonagenarians and indicates a continuous decrease of RT, PR, and GCLIPL. This data may be useful for clinical trials investigating macular diseases in older patients. Keywords: nonagenarians, SDOCT, retinal thickness, very elderly, photoreceptor, health
Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa
No full text
B3GLCT-catalyzed O-fucose glucosylation is not required for secretion of TSP1 and CTGF from retinal pigment epithelial cells
No full textChronic central serous chorioretinopathy: long-term follow-up and vision-related quality of life
No full textMyrte B Breukink,1,* Alexander JM Dingemans,1,* Anneke I den Hollander,1,2 Jan EE Keunen,1 Robert E MacLaren,3,4 Sascha Fauser,5 Giuseppe Querques,6 Carel B Hoyng,1 Susan M Downes,3,4 Camiel JF Boon1,7 1Department of Ophthalmology, 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 3Oxford Eye Hospital, Oxford University Hospitals NHS Trust, 4Nuffield Laboratory of Ophthalmology and NIHR Biomedical Research Centre, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 5Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 6Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France; 7Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands *These authors contributed equally to this work Purpose: To describe the clinical findings and long-term outcome of patients with chronic central serous chorioretinopathy (cCSC).Materials and methods: This was a retrospective case series in 52 eyes of 36 patients with a follow-up period of at least 1 year. Extensive ophthalmic examination and a validated questionnaire concerning vision-related quality of life (National Eye Institute Visual Function Questionnaire [NEI-VFQ]-39) were analyzed.Results: Mean visual acuity showed a significant decline over time of 0.16 logarithm of minimum angle of resolution ([logMAR] range: -0.22 to 1.3; P=0.009) after a mean follow-up period of 10.6 years. Also, patients reported lower vision-related quality of life based on the NEI-VFQ-39 for almost all categories compared to healthy controls. Macular atrophy was diagnosed more often on optical coherence tomography compared to other diagnostic entities. Retinal pigment epithelium detachments in the macula were documented on optical coherence tomography in 56% of the patients. A significant thinning of foveal thickness was measured over time compared to unaffected fellow eyes (P=0.002). On long-term follow-up, 13 eyes (37%) showed an increase in number of hot spots on fluorescein angiography.Conclusion: This study indicates that cCSC is a progressive disease in many patients, causing a progressive decline in visual acuity, accompanied by lower reported vision-related quality of life. In deciding whether or not to treat, the progressive nature of cCSC should be taken into account in this relatively young and often still professionally active patient group. Keywords: chronic central serous chorioretinopathy, micropulse laser, NEI-VFQ-39, PDT, vision-related quality of lif
IMPG2-Associated Retinitis Pigmentosa Displays Relatively Early Macular Involvement
No full textContains fulltext :
138202.pdf (Publisher’s version ) (Open Access)PURPOSE: To provide the first detailed clinical description in patients with RP caused by recessive mutations in IMPG2. METHODS: This international collaborative study includes 17 RP patients with inherited retinal disease caused by mutations in IMPG2. The patients were clinically (re-)examined, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, perimetry, ERG, optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, fundus photography, and color vision tests. The main outcome measures included mean age at onset, initial symptom, best-corrected visual acuity, fundus appearance, perimetry results, ERG responses, OCT images, FAF imaging, color vision test reports and DNA sequence variants. RESULTS: The mean age at onset was 10.5 years (range, 4-20 years). Initial symptoms included night blindness in 59% of patients, a decreased visual acuity in 35%, and visual field loss in 6%. Fundus abnormalities were typical of RP: optic disc pallor, attenuated vessels, bone spicules, and generalized atrophy of the retina and choriocapillaris. Additionally, we observed macular abnormalities in all patients, ranging from subtle mottling of the macular pigment epithelium (two patients) and a bull's eye maculopathy (seven patients) to macular chorioretinal atrophy (seven patients). CONCLUSIONS: Mutations in IMPG2 cause a severe form of RP with symptoms manifesting in the first 2 decades of life. IMPG2-associated RP is frequently accompanied by macular involvement, ranging from mild pigment alterations to profound chorioretinal atrophy. The resulting decrease in central vision in combination with the severe tunnel vision leads to severe visual impairment in patients with IMPG2-associated RP
2006 Author Recognition Bibliography
No full texthttps://scholarworks.gvsu.edu/authorrecognition/1008/thumbnail.jp
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