RESUMEN
Retinitis pigmentosa (RP) is a heterogenous hereditary disorder leading to blindness. Despite using next-generation sequencing technologies, causal variants in about 60% of RP cases remain unknown. The heterogeneous genetic inheritance pattern makes it difficult to pinpoint causal variants. Besides, rare penetrating variants are hardly observed in general case-control studies. Thus, a family-based analysis, specifically in a consanguineous family, is a clinically and genetically valuable approach for RP. We analyzed a Japanese consanguineous family with a member suffering from RP with a typical autosomal recessive pattern. We sequenced five direct descendants and spouse using Whole-exome sequencing (WES) and Whole-genome sequencing (WGS). We identified a homozygous pathogenic missense variant in CNGA1 (NM_000087.3, c.839G > A, p.Arg280His) in the proband, while we found no homozygous genotypes in the other family members. CNGA1 was previously reported to be associated with RP. We confirmed the genotypes by the Sanger sequencing. Additionally, we assessed the homozygous genotype in the proband for the possibility of a founder mutation using homozygosity analysis. Our results suggested the two copies of the variant derived from a founder mutation. In conclusion, we found the homozygotes for c.839G > A in CNGA1 as causal for RP.
Asunto(s)
Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Homocigoto , Retinitis Pigmentosa/genética , Consanguinidad , Femenino , Humanos , Japón , Masculino , Mutación Missense , Linaje , Secuenciación Completa del GenomaRESUMEN
Purpose: Disruption of proteostasis is a key event in many neurodegenerative diseases. Heat shock proteins (HSPs) participate in multiple functions associated with intracellular transport and proteostasis. We evaluated the effect of augmented HSP70 expression in mutant photoreceptors of mouse retinal degeneration models to test the hypothesis that failure to sustain HSP70 expression contributes to photoreceptor cell death. Methods: We examined HSP70 expression in retinas of wild-type and mutant mice by RNA and protein analysis. A transgenic mouse line, TgCrx-Hspa1a-Flag, was generated to express FLAG-tagged full-length HSP70 protein under control of a 2.3 kb mouse Crx promoter. This line was crossed to three distinct retinal degeneration mouse models. Retinal structure and function were evaluated by histology, immunohistochemistry, and electroretinography. Results: In seven different mouse models of retinal degeneration, we detected transient elevation of endogenous HSP70 expression at early stages, followed by a dramatic reduction as cell death ensues, suggesting an initial adaptive response to cellular stress. Augmented expression of HSP70 in RHOT17M mice, in which mutant rhodopsin is misfolded, marginally improved photoreceptor survival, whereas elevated HSP70 led to more severe retinal degeneration in rd10 mutants that produce a partially functional PDE6B. In Rpgrip1-/- mice that display a ciliary defect, higher HSP70 had no impact on photoreceptor survival or function. Conclusions: HSP70 overexpression has divergent effects in photoreceptors determined, at least in part, by the nature of the mutant protein each model carries. Additional investigations on HSP pathways and associated chaperone networks in photoreceptors are needed before designing therapeutic strategies targeting proteostasis.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Proteínas HSP70 de Choque Térmico/genética , Degeneración Retiniana/metabolismo , Células Fotorreceptoras Retinianas Bastones/metabolismo , Animales , Supervivencia Celular , Modelos Animales de Enfermedad , Electrorretinografía , Immunoblotting , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Fluorescente , Retina/fisiopatología , Degeneración Retiniana/fisiopatología , Células Fotorreceptoras Retinianas Bastones/fisiologíaRESUMEN
In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)121 and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. KUSs appeared to avert endoplasmic reticulum (ER) stress by maintaining ATP levels, resulting in the protection of ganglion cells from cell death. To further elucidate the protective mechanisms of KUSs, we examined gene expression profiles in affected ganglion cells. We first injected KUS-treated mice with NMDA and then isolated the affected retinal ganglion cells using fluorescence-activated cell sorting. Gene expression in the cells was quantified using a next-generation sequencer. Resultantly, we found that KUS121 upregulated several genes involved in energy metabolism. In addition, we observed the upregulation of Zfp667, which has been reported to suppress apoptosis-related genes and prevent cell death. These results further support the suitability of KUS121 as a therapeutic drug in protecting retinal ganglion cells in ophthalmic disorders, such as glaucoma.
Asunto(s)
Susceptibilidad a Enfermedades , Enfermedades de la Retina/etiología , Enfermedades de la Retina/metabolismo , Células Ganglionares de la Retina/metabolismo , Transcriptoma , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/metabolismo , Enfermedad Aguda , Animales , Apoptosis , Biomarcadores , Biología Computacional/métodos , Modelos Animales de Enfermedad , Metabolismo Energético , Perfilación de la Expresión Génica , Ontología de Genes , Inmunofenotipificación , Redes y Vías Metabólicas , Ratones , N-Metilaspartato/efectos adversos , Enfermedades de la Retina/patologíaRESUMEN
Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.
Asunto(s)
Colesterol/metabolismo , Distrofias Hereditarias de la Córnea/metabolismo , Enfermedades de la Retina/metabolismo , Animales , Colesterol/análisis , Distrofias Hereditarias de la Córnea/dietoterapia , Distrofias Hereditarias de la Córnea/enzimología , Distrofias Hereditarias de la Córnea/genética , Familia 4 del Citocromo P450/genética , Familia 4 del Citocromo P450/metabolismo , Humanos , Ratones , Mutación , Fenotipo , Enfermedades de la Retina/dietoterapia , Enfermedades de la Retina/enzimología , Enfermedades de la Retina/genética , Epitelio Pigmentado de la Retina/enzimología , Epitelio Pigmentado de la Retina/metabolismoRESUMEN
Age-related macular degeneration (AMD), in which choroidal neovascularization (CNV) affects the center of the retina (macula), leads to the irreversible visual loss. The intravitreal injection of anti-angiogenesis antibodies improved the prognosis of AMD, but relatively less invasive therapies should be explored. In the present study, we show that a high-density lipoprotein (HDL) mutant is a therapeutically active drug carrier capable of treating a posterior eye disease in mice via instillation. Various HDL mutants were prepared with apoA-I proteins fused with different cell-penetrating peptides (CPPs) and phospholipids with different alkyl chain lengths; their sizes were further controlled in the range of 10-25nm. They were screened based on the efficiency of fluorescent dye delivery to the inner retinal layer in mice. The best mutant was found to have penetratin (PEN) as a CPP, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and a size of 15nm. In preclinical studies on a laser-induced CNV murine model, 1week of instillation of the best mutant carrying the anti-angiogenesis drug pazopanib had dramatic therapeutic effects in reducing the CNV size. Importantly, the HDL mutant by itself contributed to the therapeutic effects. Future clinical trials for treating AMD with instillation of the HDL mutant are expected.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Péptidos de Penetración Celular/administración & dosificación , Neovascularización Coroidal/tratamiento farmacológico , Portadores de Fármacos/administración & dosificación , Lipoproteínas HDL/administración & dosificación , Soluciones Oftálmicas/administración & dosificación , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , Apolipoproteína A-I/genética , Cumarinas/administración & dosificación , Indazoles , Lipoproteínas HDL/genética , Liposomas , Masculino , Ratones Endogámicos C57BL , Mutación , Nanopartículas/administración & dosificación , Tiazoles/administración & dosificaciónRESUMEN
Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P-value < 1.0 × 10-5, STON1-GTF2A1L/LHCGR/FSHR, PLXNA1, CTNNA3, ARMS2/HTRA1, LHFP, and FLJ38725. The first replication study for these six regions comparing 36 bilateral and 132 unilateral Japanese cases confirmed significant associations of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR), rs2284665 (ARMS2/HTRA1), and rs8002574 (LHFP) to bilaterality. In the second replication study comparing 24 bilateral and 78 unilateral cases from Singapore, rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) only showed significant association. Meta-analysis of discovery and replication studies confirmed genome-wide level significant association (P = 2.61 × 10-9) of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) and strong associations (P = 5.76 × 10-7 and 9.73 × 10-7, respectively) of rs2284665 (ARMS2/HTRA1) and rs8002574 (LHFP). Our GWAS for neovascular AMD bilaterality found new genetic loci STON1-GTF2A1L/LHCGR/FSHR and confirmed the previously reported association of ARMS2/HTRA1.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neovascularización Patológica/genética , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/genética , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Degeneración Macular Húmeda/patologíaRESUMEN
Purpose: To examine the associations of the earlier reported glaucoma-related genes to the regional circumpapillary retinal nerve fiber layer thicknesses (cpRNFLTs) and corresponding visual field defects. Methods: We studied 756 patients with primary open-angle glaucoma (POAG) and 3094 normal controls. Each participant was genotyped for nine single nucleotide polymorphisms (SNPs) of four glaucoma-susceptible genes: the CDKN2B(AS1), TMCO1, CAV1/CAV2, and SIX1/SIX6 genes. For the SNPs that were significantly associated with the POAG case-control analyses, the associations of SNP genotypes with the cpRNFLTs of 12 sectors were also analyzed, and then finer assessments were performed using 768 points of the cpRNFLT and corresponding visual field defect sensitivities using case-only subjects. Results: We confirmed that there was a significant association of the CDKN2B(AS1) gene to POAG. For the suggested region-specific associations of these genes with the 12-sectored cpRNFLT, a 768-point cpRNFLT examination showed that rs4977756 near CDKN2B had significant signal peaks in the temporal region at 330° to 360° and 0° to 30° (maximum ß = 2.92, P = 2.9 × 10-5 at 351.1° and maximum ß = 3.97, P = 2.2 × 10-4 at 23.4°, respectively). These region-specific signals were validated by the corresponding visual field defect patterns of the paracentral/lower hemifield (P < 0.05). Conclusions: Genetic association analyses using the cpRNFLT with 768 points suggest that the CDKN2B gene was associated with paracentral/lower hemifield scotomas. Our regional association analyses on cpRNFLT allow detailed characterization of glaucoma-related genes and should be a new target for genomic studies for glaucoma endophenotypes.
Asunto(s)
Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Glaucoma de Ángulo Abierto/genética , Fibras Nerviosas/patología , Polimorfismo Genético , Células Ganglionares de la Retina/patología , Escotoma/genética , Campos Visuales , Canales de Calcio , Caveolina 1 , Caveolina 2 , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Glaucoma de Ángulo Abierto/complicaciones , Glaucoma de Ángulo Abierto/metabolismo , Proteínas de Homeodominio , Humanos , Presión Intraocular , Proteínas de la Membrana/genética , Fenotipo , Escotoma/etiología , Escotoma/metabolismo , TransactivadoresRESUMEN
Ophthalmologists sometimes face difficulties in identifying the origin of visual acuity (VA) loss in a retinitis pigmentosa (RP) patient, particularly before cataract surgery: cataract or the retinal disease state. Therefore, it is important to identify the significant factors correlating with VA. Nowadays, retinal blood flow in superficial and deep layers can be estimated non-invasively using optical coherence tomography angiography (OCTA). We estimated blood flow per retinal layer by using OCTA; investigated the correlation between VA and other parameters including blood flow and retinal thickness; and identified the most associated factor with VA in patients with RP. OCTA images in 68 of consecutive 110 Japanese RP patients were analysable (analysable RP group). Thirty-two age- and axial length-matched healthy eyes (control group) were studied. In the analysable RP group, the parafoveal flow density in superficial and deep layers was 47.0 ± 4.9% and 52.4 ± 5.5%, respectively, which was significantly lower than that in controls. Using multivariate analysis, we found that the parafoveal flow density in the deep layer and superficial foveal avascular area were the factors associated with VA. Non-invasive estimation of retinal blood flow per retinal layer using OCTA is useful for predicting VA in RP patients.
Asunto(s)
Angiografía por Tomografía Computarizada/métodos , Fóvea Central/irrigación sanguínea , Retinitis Pigmentosa/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodos , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Fóvea Central/diagnóstico por imagen , Fondo de Ojo , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Flujo Sanguíneo RegionalRESUMEN
PURPOSE: In this study, we aimed to detect mutations in the SLC7A14 cationic transporter gene, which has recently been reported as a causative gene for retinitis pigmentosa (RP), in Japanese patients with autosomal recessive (AR) or sporadic RP. MATERIALS AND METHODS: We included 146 unrelated Japanese patients with AR or sporadic RP who lacked mutations in genes known to be associated with RP despite next-generation sequencing-based screening. We sequenced the seven SLC7A14 coding exons along with their flanking intronic DNA using the Sanger method. The detected polymorphisms were assessed for their pathogenicity with in silico prediction tools. For those who had heterozygous, nonsynonymous variants, we performed multiplex ligation-dependent probe amplification (MLPA) to search for additional deletion/duplication. RESULTS: We detected four distinct SLC7A14 polymorphisms excluding synonymous polymorphisms. Two of these polymorphisms were assessed as detrimental by in silico prediction tools. However, all of the mutations were heterozygous. Neither homozygous polymorphisms nor compound heterozygous polymorphisms, which are considered detrimental variants, were detected. Neither deletion nor duplication was found with MLPA in patients with heterozygous variants. CONCLUSIONS: The four SLC7A14 mutations detected herein were unlikely to be pathogenic in this Japanese cohort. The frequency and pathogenicity of SLC7A14 mutations may vary depending on ethnicity, and these mutations may be rare in Japanese patients.
Asunto(s)
Sistema de Transporte de Aminoácidos y+/genética , Genes Recesivos , Polimorfismo de Nucleótido Simple , Retinitis Pigmentosa/genética , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/etnología , Análisis Mutacional de ADN , Exones/genética , Femenino , Heterocigoto , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Retinitis Pigmentosa/etnología , Adulto JovenRESUMEN
PURPOSE: To compare atrophy of the choroid and retina between Bietti crystalline dystrophy (BCD) patients and EYS-related retinitis pigmentosa (RP) patients with a similar degree of central visual field defects, age, and axial length (AL). METHODS: Nine eyes of nine BCD patients with CYP4V2 mutations (BCD group) were examined. Moreover, we selected 10 eyes of 10 RP patients with EYS mutations matched for age, axial length, and mean deviation (measured with the 10-2 SITA standard program; EYS-RP group), and 10 eyes of 10 normal volunteers matched for age and axial length (control group). Macular thicknesses of the choroid and retina were measured via swept-source optical coherence tomography. RESULTS: The macular choroid was significantly thinner in the BCD group than in the EYS-RP and control groups, although the thickness did not significantly differ between the EYS-RP and control groups. The macular retina was significantly thinner in the BCD and EYS-RP groups than in the control group, although the thickness did not significantly differ between the BCD and EYS-RP groups at most sites. CONCLUSION: Bietti crystalline dystrophy patients with CYP4V2 mutations showed more severe macular choroid atrophy as compared to EYS-related RP patients. These different damage patterns suggest differences in choroidal expression between CYP4V2 and EYS.
Asunto(s)
Coroides/patología , Distrofias Hereditarias de la Córnea/genética , Familia 4 del Citocromo P450/genética , Proteínas del Ojo/genética , Mácula Lútea/patología , Mutación , Enfermedades de la Retina/genética , Retinitis Pigmentosa/genética , Anomalías Múltiples , Adulto , Anciano , Atrofia/patología , Lámina Basal de la Coroides/patología , Distrofias Hereditarias de la Córnea/diagnóstico , Familia 4 del Citocromo P450/metabolismo , ADN/genética , Análisis Mutacional de ADN , Proteínas del Ojo/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Retina/diagnóstico , Retinitis Pigmentosa/diagnóstico , Tomografía de Coherencia ÓpticaRESUMEN
AIMS: To evaluate retinal arterial wall thickness (WT) using high-resolution retinal imaging in patients with type 2 diabetes and assess its correlation with risk factors for arteriosclerosis. METHODS: Outer diameter, inner diameter and WT of the retinal artery were measured using adaptive optics scanning laser ophthalmoscopy in 28 patients with type 2 diabetes without clinically apparent diabetic retinopathy and normal volunteers. Laboratory values and intima-media thickness (IMT) in the common carotid artery were measured. RESULTS: Retinal arterial WT was significantly greater in patients with type 2 diabetes than in controls (p=0.02). There was a significant correlation of retinal artery WT with IMT in patients with diabetes (r=0.40, p=0.04). WT in patients with diabetes was positively correlated with haemoglobin A1c (HbA1c) (r=0.49, p=0.001), total cholesterol (r=0.47, p=0.002) and low-density lipoprotein cholesterol (r=0.47, p=0.003). CONCLUSIONS: Microvasuclar thickness was greater in patients with diabetes than in controls. Furthermore, WT was positively correlated with HbA1c, total cholesterol and low-density lipoprotein cholesterol levels and IMT in the diabetic group. These results suggest that retinal artery wall measurements can be potential surrogate markers of early diabetic microangiopathy.
Asunto(s)
Aterosclerosis/patología , Arteria Carótida Común/patología , Diabetes Mellitus Tipo 2/complicaciones , Arteria Retiniana/patología , Adulto , Anciano , Aterosclerosis/etiología , Grosor Intima-Media Carotídeo , Estudios Transversales , Diabetes Mellitus Tipo 2/patología , Angiopatías Diabéticas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. Given that the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone-like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal days 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously unannotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas del Ojo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Fotorreceptoras Retinianas Conos/metabolismo , Transcriptoma/genética , Empalme Alternativo/genética , Animales , Animales Recién Nacidos , Diferenciación Celular/genética , Simulación por Computador , Metilación de ADN/genética , Redes Reguladoras de Genes , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Anotación de Secuencia Molecular , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
PURPOSE: To investigate the efficacy of targeted exome sequencing for mutational screening of Japanese patients with cone dystrophy (CD) or cone-rod dystrophy (CRD). METHODS: DNA samples from 43 Japanese patients with CD or CRD were sequenced using an exome-sequencing panel targeting all 193 known inherited eye disease genes and next-generation sequencing methodologies. Subsequently, candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed using distinct filtering approaches, which included the frequency of the variants in normal populations, in silico prediction tools, and cosegregation. RESULTS: Causative mutations were detected in 12 patients with CD or CRD (27.9%). In total, 14 distinct mutations were identified in the genes ABCA4, CDHR1, CRB1, CRX, GUCY2D, KCNV2, PROM1, PRPH2, and RDH5, including four novel mutations, c.3050+1G>A in ABCA4, c.386A>G in CDHR1, c.652+1_652+4del in CRB1, and c.454G>A in KCNV2. Moreover, a putative pathogenic mutation was identified in RGS9BP, a gene recognized as the source of bradyopsia. CONCLUSIONS: Targeted exome sequencing effectively identified causative mutations in Japanese patients with CD or CRD. The results confirmed the heterogeneity of the genes responsible for CD and CRD in Japanese populations, as well as the efficacy of targeted exome sequencing-based screening of patients with inherited retinal degeneration.
Asunto(s)
Proteínas del Ojo/genética , Mutación , Retinitis Pigmentosa/genética , Pueblo Asiatico/genética , Análisis Mutacional de ADN , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón/epidemiología , Masculino , Técnicas de Diagnóstico Molecular , Linaje , Retinitis Pigmentosa/diagnóstico , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
PURPOSE: We evaluated the efficacy of column scatter plots to describe genotype-phenotype correlations in a Japanese cohort with retinitis pigmentosa (RP). METHODS: Clinical records of 121 patients with RP with identified causative mutations were reviewed. Visual acuity, central and peripheral visual fields, electroretinography (ERG), lens status, and measurements of optical coherence tomography were evaluated according to causative genes using column scatter plots. Values for three common genes (EYS, USH2A, and RHO) were compared statistically. RESULTS: All patients with PDE6B, PRPH2, and RPGR mutations, those 55 years old or younger with RP1L1 and USH2A mutations, and those 45 years old or younger with EYS and RHO mutations retained visual acuity of at least 0.1. All patients with RPGR mutations showed at least -20 dB mean deviation. Goldmann perimeter measures of 4/6 patients with RHO mutations showed remaining peripheral visual fields. Dark-adapted 0.01 and 3.0 ERGs were extinguished for most genes. Half of the patients with RHO RP maintained cone responses in light-adapted 3.0 and 3.0 flicker ERG. All patients with PRPH2, those 55 years old or younger with USH2A and RP1L1, and those 45 years old or younger with PDE6B and EYS mutations maintained subfoveal ellipsoid zones. No differences were identified between EYS and USH2A or RHO and USH2A. CONCLUSIONS: Column scatter plots enabled comparisons of the associated severities and illustration of the ophthalmological measurements for every RP causative gene. TRANSLATIONAL RELEVANCE: Analysis of mutations in specific genes may be helpful for determining visual prognoses in the clinical setting.
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Glaucoma de Ángulo Abierto/genética , Miopía Degenerativa/genética , ARN Largo no Codificante/genética , Pueblo Asiatico/etnología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Técnicas de Genotipaje , Glaucoma de Ángulo Abierto/etnología , Humanos , Presión Intraocular , Japón/epidemiología , Masculino , Persona de Mediana Edad , Miopía Degenerativa/etnologíaRESUMEN
To examine the similarity of wide-field fundus autofluorescence (FAF) imaging in inherited retinal dystrophy between siblings and between parents and their children. The subjects included 17 siblings (12 with retinitis pigmentosa and 5 with cone rod dystrophy) and 10 parent-child pairs (8 with retinitis pigmentosa and 2 with cone rod dystrophy). We quantified the similarity of wide-field FAF using image processing techniques of cropping, binarization, superimposition, and subtraction. The estimated similarity of the siblings was compared with that of the parent-child pairs and that of the age-matched unrelated patients. The similarity between siblings was significantly higher that of parent-child pairs or that of age-matched unrelated patients (P = 0.004 and P = 0.049, respectively). Wide-field FAF images were similar between siblings with inherited retinal dystrophy but different between parent-child pairs. This suggests that aging is a confounding factor in genotype-phenotype correlation studies.
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Fluorescencia , Fondo de Ojo , Lipofuscina/química , Distrofias Retinianas/diagnóstico , Factores de Edad , Salud de la Familia , Estudios de Asociación Genética , Genotipo , Humanos , Lipofuscina/metabolismo , Microscopía Confocal , Oftalmoscopía , Fenotipo , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Epitelio Pigmentado de la Retina/química , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Hermanos , Tomografía de Coherencia ÓpticaRESUMEN
BACKGROUND: Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic ß-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia. METHODS: A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. RESULTS: As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥12 h, P<0.001) or near-fasting (5-11 h, P<0.001) conditions, and not in those taken under non-fasting (<5 h, P=0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (ß=0.052, P<0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA(â)glucose; ß=0.036, P<0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s. CONCLUSIONS: Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature.
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Glucemia/análisis , Ácidos Grasos no Esterificados/sangre , Rigidez Vascular , Adulto , Anciano , Índice Tobillo Braquial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de la Onda del PulsoRESUMEN
PURPOSE: To evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO). DESIGN: Prospective observational case series with comparison to healthy controls. METHODS: Seven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied. All participants underwent ophthalmologic examinations and AO-SLO assessments. All patients underwent spectral-domain optical coherence tomography, fundus autofluorescence, Humphrey field analysis, and electroretinography. AO-SLO images were analyzed 0.5 mm and 1.0 mm from the center of the fovea in the superior, inferior, nasal, and temporal quadrants. RESULTS: Mean ± standard deviation cone density (cells/mm(2)) 0.5 mm from the center of the fovea was 17,209 ± 2276 in patients and 20 493 ± 2758 in controls, which was statistically different (P = .001); however, mean cone density 1.0 mm from the center of the fovea was 15 685 ± 2302 in patients and 15 705 ± 1848 in controls, which was not statistically different (P = .20). There was no correlation between cone density and mean deviation measured using a Humphrey field analysis or visual acuity in patients. CONCLUSIONS: In Bietti crystalline dystrophy patients with CYP4V2 mutations, cone density remained for visual dysfunction by evaluation using high-resolution AO-SLO. These findings support the theory that disorder of the retinal pigment epithelium and the photoreceptors in the patients are the primary and secondary pathologic changes, respectively. This is consistent with results from previous basic studies.
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Distrofias Hereditarias de la Córnea/diagnóstico , Distrofias Hereditarias de la Córnea/genética , Sistema Enzimático del Citocromo P-450/genética , Mutación , Células Fotorreceptoras de Vertebrados/patología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Familia 4 del Citocromo P450 , Electrorretinografía , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Oftalmoscopía , Estudios Prospectivos , Epitelio Pigmentado de la Retina/patología , Tomografía de Coherencia Óptica , Pruebas del Campo Visual , Campos Visuales/fisiologíaRESUMEN
OBJECTIVES: We undertook descriptive epidemiology of spot urine sodium-to-potassium ratio (Na/K) in a population sample to clarify the close relationship between Na/K and blood pressure level independently of potential confounding factors. METHODS: Study participants consisted of 9144 apparently healthy citizens (aged 54â±â13 years). All clinical parameters were obtained at baseline. RESULTS: Na/K was significantly higher in hypertensive individuals irrespective of antihypertensive medication status (normotension, 3.12â±â1.82; untreated hypertension 3.50â±â1.96; treated hypertension, 3.72â±â2.53). As urinary Na (ßâ=â0.092, Pâ<â0.001) and K (ßâ=â-0.050, Pâ<â0.001) levels were inversely associated with BP, Na/K (ßâ=â0.118, Pâ<â0.001) was more closely associated with BP than Na or K alone, as well as daily salt intake estimated from urinary Na (ßâ=â0.088, Pâ<â0.001). Several factors were significantly associated with Na/K, namely age, sex, obesity, blood pressure, renal function, salt restriction status, serum phosphate and urinary creatinine level, and fasting period and season at urine sample collection. However, the association between Na/K and BP was independent of these factors (adjusted ßâ=â0.112, Pâ<â0.001). No direct association was observed between Na/K and large arterial remodeling assessed by pulse wave analysis (Pâ=â0.496) or retinal arteriolar morphological change (Pâ=â0.431). Further, a genome-wide association study failed to identify any particular genotype influencing urinary Na and K levels. CONCLUSIONS: Although we clarified several factors that might affect spot urine Na/K, these relationships were not substantial enough to confound the association between urinary Na/K and BP. A simple measure of Na/K might be more representative of salt loading obtained from spot urine samples than Na excretion alone.
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Presión Sanguínea , Hipertensión/fisiopatología , Potasio/orina , Sodio/orina , Adulto , Anciano , Arterias/fisiopatología , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hipertensión/epidemiología , Hipertensión/genética , Japón/epidemiología , Masculino , Persona de Mediana Edad , Análisis de la Onda del Pulso , Cloruro de Sodio Dietético/farmacología , Sodio en la Dieta , Remodelación VascularRESUMEN
We screened patients with choroideremia using next-generation sequencing (NGS) and identified a novel mutation and a known mutation in the CHM gene. One patient presented an atypical fundus appearance for choroideremia. Another patient presented macular hole retinal detachment in the left eye. The present case series shows the utility of NGS-based screening in patients with choroideremia. In addition, the presence of macular hole in 1 of the 2 patients, together with a previous report, indicated the susceptibility of patients with choroideremia to macular hole.