Publications by authors named "Takeshi Iwata"

146 Publications

Clinical course of a Japanese girl with Leber congenital amaurosis associated with a novel nonsense pathogenic variant in : a case report and mini review.

Ophthalmic Genet 2022 Jan 13:1-9. Epub 2022 Jan 13.

Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka, Japan.

   Leber congenital amaurosis (LCA), although rare, is one of the most severe forms of early-onset inherited retinal dystrophy (IRD). Here, we review the molecular genetics and phenotypic characteristics of patients with associated IRD. The longitudinal clinical and molecular findings of a Japanese girl diagnosed with LCA associated with pathogenic variants in c.648delG, (p.Trp216Ter*) and c.709C>T (p.Arg237Cys) have been described to highlight the salient clinical features of -associated IRD.
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http://dx.doi.org/10.1080/13816810.2021.2023195DOI Listing
January 2022

Visual Field Characteristics in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report No. 3.

Invest Ophthalmol Vis Sci 2022 01;63(1):12

Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.

Purpose: The purpose of this study was to investigate the perimetric features and their associations with structural and functional features in patients with RP1L1-associated occult macular dystrophy (OMD; i.e. Miyake disease).

Methods: In this international, multicenter, retrospective cohort study, 76 eyes of 38 patients from an East Asian cohort of patients with RP1L1-associated OMD were recruited. Visual field tests were performed using standard automated perimetry, and the patients were classified into three perimetric groups based on the visual field findings: central scotoma, other scotoma (e.g. paracentral scotoma), and no scotoma. The association of the structural and functional findings with the perimetric findings was evaluated.

Results: Fifty-four eyes (71.1%) showed central scotoma, 14 (18.4%) had other scotomata, and 8 (10.5%) had no scotoma. Central scotoma was mostly noted in both eyes (96.3%) and within the central 10 degrees (90.7%). Among the three perimetric groups, there were significant differences in visual symptoms, best-corrected visual acuity (BCVA), and structural phenotypes (i.e. severity of photoreceptor changes). The central scotoma group showed worse BCVA often with severe structural abnormalities (96.3%) and a pathogenic variant of p.R45W (72.2%). The multifocal electroretinogram (mfERG) groups largely corresponded with the perimetric groups; however, 8 (10.5%) of 76 eyes showed mfERG abnormalities preceding typical central scotoma.

Conclusions: The patterns of scotoma with different clinical severity were first identified in occult macular dystrophy, and central scotoma, a severe pattern, was most frequently observed. These perimetric patterns were associated with the severity of BCVA, structural phenotypes, genotype, and objective functional characteristics which may precede in some cases.
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http://dx.doi.org/10.1167/iovs.63.1.12DOI Listing
January 2022

A Japanese boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-associated retinal disorder.

Hum Genome Var 2021 Dec 17;8(1):46. Epub 2021 Dec 17.

Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

2p15p16.1 microdeletion syndrome is a recently recognized congenital disorder characterized by developmental delay and dysmorphic features. RP2-associated retinal disorder (RP2-RD) is an X-linked inherited retinal disease with a childhood onset caused by a loss-of-function variant in the RP2 gene. Here, we describe a 14-year-old boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-RD. The recurrence risk of each condition and the indication for potential therapeutic options for RP2-RD are discussed.
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http://dx.doi.org/10.1038/s41439-021-00178-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683409PMC
December 2021

Genetic and Phenotypic Landscape of -Associated Retinal Dystrophy in Japan.

Genes (Basel) 2021 11 18;12(11). Epub 2021 Nov 18.

Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan.

() is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with -associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40's; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.
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http://dx.doi.org/10.3390/genes12111817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624169PMC
November 2021

Protein Data Bank Japan: Celebrating our 20th anniversary during a global pandemic as the Asian hub of three dimensional macromolecular structural data.

Protein Sci 2022 01 27;31(1):173-186. Epub 2021 Oct 27.

Institute for Protein Research, Osaka University, Suita, Osaka, Japan.

Protein Data Bank Japan (PDBj), a founding member of the worldwide Protein Data Bank (wwPDB) has accepted, processed and distributed experimentally determined biological macromolecular structures for 20 years. During that time, we have continuously made major improvements to our query search interface of PDBj Mine 2, the BMRBj web interface, and EM Navigator for PDB/BMRB/EMDB entries. PDBj also serves PDB-related secondary database data, original web-based modeling services such as Homology modeling of complex structure (HOMCOS), visualization services and utility tools, which we have continuously enhanced and expanded throughout the years. In addition, we have recently developed several unique archives, BSM-Arc for computational structure models, and XRDa for raw X-ray diffraction images, both of which promote open science in the structural biology community. During the COVID-19 pandemic, PDBj has also started to provide feature pages for COVID-19 related entries across all available archives at PDBj from raw experimental data and PDB structural data to computationally predicted models, while also providing COVID-19 outreach content for high school students and teachers.
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http://dx.doi.org/10.1002/pro.4211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740847PMC
January 2022

Genotype-Phenotype Correlations in -Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Department of Ophthalmology, The Jikei University School of Medicine, 3-19-18, Nishi-shimbashi, Minato-ku, Tokyo 105-8471, Japan.

Background: Little is known about genotype-phenotype correlations of -associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of variants and provide a detailed description of the clinical findings in Japanese patients.

Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD.

Results: We identified 18 pathogenic variants, including seven novel variants. Interestingly, the element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients.

Conclusions: Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the element insertion was the most major variant in Japanese patients with -associated retinal dystrophies.
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http://dx.doi.org/10.3390/jcm10112265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197273PMC
May 2021

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques.

Br J Ophthalmol 2021 09 20;105(9):1272-1279. Epub 2021 Apr 20.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

Background/aims: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging.

Methods: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (), retinitis pigmentosa () and occult macular dystrophy (). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (, , and normal).

Results: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively.

Conclusion: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380883PMC
September 2021

Binding of Gtf2i-β/δ transcription factors to the ARMS2 gene leads to increased circulating HTRA1 in AMD patients and in vitro.

J Biol Chem 2021 Jan-Jun;296:100456. Epub 2021 Feb 24.

Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. Electronic address:

The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-β/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.
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http://dx.doi.org/10.1016/j.jbc.2021.100456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039566PMC
August 2021

A new PDE6A missense variant p.Arg544Gln in rod-cone dystrophy.

Doc Ophthalmol 2021 08 21;143(1):107-114. Epub 2021 Feb 21.

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.

Purpose: Thus far, only one Japanese patient with autosomal recessive rod-cone dystrophy (AR-RCD) associated with the phosphodiesterase 6A gene (PDE6A) has been reported. The purpose of this study was to analyze the clinical features of a Japanese female patient with AR-RCD with a novel missense variant in PDE6A.

Methods: We performed whole-exome sequencing (WES) to identify the disease-causing variant and a comprehensive ophthalmic examination including full-field electroretinography (ERG).

Results: WES analysis revealed that the patient carried a novel homozygous missense variant (c.1631G > A; p.Arg544Gln) in PDE6A. Her unaffected parents carried the heterozygous variant. The patient reported night blindness in her early 20 s. At the age of 25 years, she underwent a comprehensive ophthalmic examination. Her corrected visual acuity was 20/13 in the right and 20/10 in the left eyes. Fundus images showed degenerative changes with bone spicule pigmentation in the mid-peripheral retina, and peripheral retinal vessels were not attenuated. Ultra-wide-field fundus autofluorescence images demonstrated large hypoautofluorescent regions corresponding to the degenerative changes, surrounded by hyperautofluorescence. Cross-sectional optical coherence tomography demonstrated a preserved ellipsoid zone and retinal thickness in the center of the macula, with perifoveal atrophy. ERG responses were subnormal, revealing that rod-mediated responses were more affected than cone-mediated responses, consistent with findings observed in RCD.

Conclusions: This is the second case of a patient with AR-RCD associated with PDE6A in the Japanese population. These findings will contribute to a better clinical understanding of PDE6A-associated RCD and valuable insights for gene therapy trials.
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http://dx.doi.org/10.1007/s10633-021-09826-yDOI Listing
August 2021

The Serine Protease HTRA-1 Is a Biomarker for ROP and Mediates Retinal Neovascularization.

Front Mol Neurosci 2020 17;13:605918. Epub 2020 Nov 17.

Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT, United States.

Retinopathy of prematurity (ROP) is a blinding aberrancy of retinal vascular maturation in preterm infants. Despite delayed onset after preterm birth, representing a window for therapeutic intervention, we cannot prevent or cure ROP blindness. A natural form of ROP protection exists in the setting of early-onset maternal preeclampsia, though is not well characterized. As ischemia is a central feature in both ROP and preeclampsia, we hypothesized that angiogenesis mediators may underlie this protection. To test our hypothesis we analyzed peripheral blood expression of candidate proteins with suggested roles in preeclamptic and ROP pathophysiology and with a proposed angiogenesis function (HTRA-1, IGF-1, TGFβ-1, and VEGF-A). Analysis in a discovery cohort of 40 maternal-infant pairs found that elevated HTRA-1 (high-temperature requirement-A serine peptidase-1) was significantly associated with increased risk of ROP and the absence of preeclampsia, thus fitting a model of preeclampsia-mediated ROP protection. We validated these findings and further demonstrated a dose-response between systemic infant HTRA-1 expression and risk for ROP development in a larger and more diverse validation cohort consisting of preterm infants recruited from two institutions. Functional analysis in the oxygen-induced retinopathy (OIR) murine model of ROP supported our systemic human findings at the local tissue level, demonstrating that HtrA-1 expression is elevated in both the neurosensory retina and retinal pigment epithelium by RT-PCR in the ROP disease state. Finally, transgenic mice over-expressing HtrA-1 demonstrate greater ROP disease severity in this model. Thus, HTRA-1 may underlie ROP protection in preeclampsia and represent an avenue for disease , which does not currently exist.
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http://dx.doi.org/10.3389/fnmol.2020.605918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705345PMC
November 2020

Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families.

Sci Rep 2020 09 28;10(1):15883. Epub 2020 Sep 28.

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.

Choroideremia (CHM) is an incurable progressive chorioretinal dystrophy. Little is known about the natural disease course of visual acuity in the Japanese population. We aimed to investigate the genetic spectrum of the CHM gene and visual acuity outcomes in 24 CHM patients from 16 Japanese families. We measured decimal best-corrected visual acuity (BCVA) at presentation and follow-up, converted to logMAR units for statistical analysis. Sanger and/or whole-exome sequencing were performed to identify pathogenic CHM variants/deletions. The median age at presentation was 37.0 years (range, 5-76 years). The mean follow-up interval was 8.2 years. BCVA of the better-seeing eye at presentation was significantly worsened with increasing age (r = 0.515, p < 0.01), with a high rate of BCVA decline in patients > 40 years old. A Kaplan-Meier survival curve suggested that a BCVA of Snellen equivalent 20/40 at follow-up remains until the fifties. Fourteen pathogenic variants, 6 of which were novel [c.49 + 5G > A, c.116 + 5G > A, p.(Gly176Glu, Glu177Ter), p.Tyr531Ter, an exon 2 deletion, and a 5.0-Mb deletion], were identified in 15 families. No variant was found in one family only. Our BCVA outcome data are useful for predicting visual prognosis and determining the timing of intervention in Japanese patients with CHM variants.
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http://dx.doi.org/10.1038/s41598-020-72623-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522719PMC
September 2020

RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association.

Am J Med Genet C Semin Med Genet 2020 09 1;184(3):675-693. Epub 2020 Sep 1.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.
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http://dx.doi.org/10.1002/ajmg.c.31830DOI Listing
September 2020

Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with -Associated Retinal Disorder.

Transl Vis Sci Technol 2020 05 11;9(6). Epub 2020 May 11.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan.

Purpose: To determine the clinical and genetic characteristics of patients with -associated retinal disorder (-RD).

Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]).

Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys).

Conclusions: This large cohort study delineates the disease spectrum of -RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of -RD for ADCORD and ARLCA in the Japanese population was revealed.

Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.
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http://dx.doi.org/10.1167/tvst.9.6.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408927PMC
May 2020

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population.

Am J Med Genet C Semin Med Genet 2020 09 20;184(3):656-674. Epub 2020 Aug 20.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.
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http://dx.doi.org/10.1002/ajmg.c.31826DOI Listing
September 2020

Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2.

Am J Ophthalmol 2021 01 21;221:169-180. Epub 2020 Jul 21.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address:

Purpose: To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease).

Design: An international multicenter retrospective cohort study.

Methods: Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone).

Results: There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P = .005) and shorter disease duration (P = .002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P < .001).

Conclusions: A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.
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http://dx.doi.org/10.1016/j.ajo.2020.07.025DOI Listing
January 2021

Progress of macular atrophy during 30 months' follow-up in a patient with spinocerebellar ataxia type1 (SCA1).

Doc Ophthalmol 2021 02 9;142(1):87-98. Epub 2020 Jul 9.

Department of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Purpose: To report the 30-months' course of macular dystrophy in a patient with genetically confirmed spinocerebellar ataxia type1 (SCA1).

Methods: Detailed ophthalmological examinations including best-corrected visual acuity (BCVA), perimetry, multimodal fundus imaging, and electrophysiological recordings were performed on a 52-year-old woman with SCA1. The number of CAG sequence repeats of the candidate gene was verified.

Results: The baseline decimal BCVA was 0.2 OD and 0.3 OS. Goldman perimetry showed relative central scotomas and slight enlargements of Mariotte blind spot bilaterally. Ophthalmoscopy revealed no abnormalities in the macula and optic disk. Fundus autofluorescence (FAF) showed a circular hyperautofluorescence and round-shaped hypoautofluorescence in the macula. Optical coherence tomography (OCT) showed a loss of the interdigitation zone and ellipsoid zone (EZ) in the macula. Full-field scotopic and photopic Full-field electroretinograms (ERGs) were normal, and multifocal ERGs were decreased in the central area. After 30 months, the BCVA had not changed, but the FAF showed a spark-like hypoautofluorescence in the macula. The abnormal area of the EZ had expanded toward the periphery, and the rate of EZ loss was 199.7%/year OD and 206.8%/year OS. Genetic examinations revealed an increase in the number of heterozygous CAG repeats in the ATXN1 gene, and the CAG repeat number of the mutant allele ranged from 43 to 48.

Conclusions: The full-field scotopic and photopic ERGs were normal. The mfERGs were significantly smaller in the central region. OCT demonstrated bilateral photoreceptor atrophy in the macula, and the rate of EZ loss was more rapid than in other macular dystrophies. Spark-like hypoautofluorescence appeared during the course of the disease process which might be a specific feature of SCA1-related retinopathy.
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http://dx.doi.org/10.1007/s10633-020-09782-zDOI Listing
February 2021

Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association.

Sci Rep 2020 06 12;10(1):9531. Epub 2020 Jun 12.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, 152-8902, Japan.

Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, -0.08-2.00/-0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.
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http://dx.doi.org/10.1038/s41598-020-65737-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293272PMC
June 2020

Novel homozygous CLN3 missense variant in isolated retinal dystrophy: A case report and electron microscopic findings.

Mol Genet Genomic Med 2020 08 22;8(8):e1308. Epub 2020 May 22.

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.

Background: Biallelic CLN3 gene variants have been found in either juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or isolated retinal dystrophy. It has been reported that most JNCL patients carry a common 1.02-kb deletion variant homozygously. Clinical characteristics of patients with biallelic CLN3 missense variants are not well elucidated.

Methods: We described a 26-year-old Japanese male patient with isolated retinal dystrophy. Whole-exome sequencing (WES) and transmission electron microscopy (TEM) were performed.

Results: Whole-exome sequencing identified a novel homozygous CLN3 missense variant [c.482C>T; p.(Ser161Leu)]. Ophthalmoscopy revealed retinal degeneration and macular atrophy, and later attenuated retinal vessels. Severely reduced responses were observed in both rod and cone electroretinograms. In TEM of the patient's lymphocytes, fingerprint profiles, which are specific findings in CLN3-associated JNCL, were observed in 16/624 (2.56%) lymphocytes of the patient, who has never exhibited neurological signs during the 13-year follow-up period.

Conclusion: Our results indicated that this novel CLN3 missense variant is associated with teenage-onset isolated retinal dystrophy. This is the first report of any patient with CLN3-associated disorder in the Japanese population. Although fingerprint profiles have never been reported in CLN3-associated isolated retinal dystrophy, these profiles were observed, albeit infrequently, suggesting that frequency of the fingerprint profiles might depend on variant types.
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http://dx.doi.org/10.1002/mgg3.1308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434607PMC
August 2020

RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort.

Invest Ophthalmol Vis Sci 2020 03;61(3):53

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Purpose: To investigate clinical characteristics of RDH5-related fundus albipunctatus (FAP) in a Japanese cohort.

Methods: Twenty-five patients from 22 pedigrees with RDH5-related FAP were studied. Ophthalmic medical records were reviewed. For genetic analysis, either Sanger sequencing of the RDH5 gene or whole-exome sequencing was performed.

Results: Genetic analysis identified eight different RDH5 variants, including seven known RDH5 variants (p.G35S, p.G107R, p.R167H, p.A240GfsX19, p.R278X, p.R280H, and p.L310delinsEV) and a novel variant: c.259C>T (p.Q87X). The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles). Of 50 eyes examined, 44 eyes (88.0%) showed logMAR best-corrected visual acuity (BCVA) of 0.10 or better. In optical coherence tomography, macular involvement was observed in 12 patients (24 eyes). Ten patients (83.3%) who had good BCVA (0.10 or better) exhibited diffuse disruption of the outer retina with foveal sparing, and two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA. Among the 24 eyes, ring-or crescent-shaped hyperautofluorescence or irregular autofluorescence around the fovea was observed in 15 eyes (83.3%) of 18 eyes examined by fundus autofluorescence imaging. Full-field electroretinography showed extinguished or severely decreased rod responses in all 23 examined patients, whereas decreased cone responses were seen in 17 patients (73.9%).

Conclusions: Multimodal imaging and electroretinography of RDH5-related FAP revealed high frequencies of macular involvement in older patients and decreased cone responses. Our findings suggest that progressive macular/cone dysfunction, as well as delayed rod function, may be key phenotypic features of RDH5-related FAP.
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http://dx.doi.org/10.1167/iovs.61.3.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401827PMC
March 2020

Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency.

Sci Rep 2020 03 26;10(1):5497. Epub 2020 Mar 26.

Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, 152-8902, Japan.

Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.
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http://dx.doi.org/10.1038/s41598-020-62119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099090PMC
March 2020

Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma.

Am J Ophthalmol 2020 07 23;215:135-140. Epub 2020 Mar 23.

Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan.

Purpose: We sought to investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG).

Design: Case-control genetic association study.

Methods: Japanese POAG patients (n = 505) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated.

Results: There was a significant association (P = .014; odds ratio 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P = .0014; β = -0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased.

Conclusion: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma).
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http://dx.doi.org/10.1016/j.ajo.2020.03.014DOI Listing
July 2020

Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with -Associated Retinopathy.

Int J Mol Sci 2020 Feb 16;21(4). Epub 2020 Feb 16.

Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan.

-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the gene is unexplained. We found three unrelated patients with a disease-causing variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. and were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel variants were identified. TEM of the lymphocytes of and showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the -associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of mutations may be compensable and have variations.
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http://dx.doi.org/10.3390/ijms21041331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072995PMC
February 2020

BioMagResBank (BMRB) as a Resource for Structural Biology.

Methods Mol Biol 2020 ;2112:187-218

BMRB, Biochemistry Department, University of Wisconsin-Madison, Madison, WI, USA.

The Biological Magnetic Resonance Data Bank (BioMagResBank or BMRB), founded in 1988, serves as the archive for data generated by nuclear magnetic resonance (NMR) spectroscopy of biological systems. NMR spectroscopy is unique among biophysical approaches in its ability to provide a broad range of atomic and higher-level information relevant to the structural, dynamic, and chemical properties of biological macromolecules, as well as report on metabolite and natural product concentrations in complex mixtures and their chemical structures. BMRB became a core member of the Worldwide Protein Data Bank (wwPDB) in 2007, and the BMRB archive is now a core archive of the wwPDB. Currently, about 10% of the structures deposited into the PDB archive are based on NMR spectroscopy. BMRB stores experimental and derived data from biomolecular NMR studies. Newer BMRB biopolymer depositions are divided about evenly between those associated with structure determinations (atomic coordinates and supporting information archived in the PDB) and those reporting experimental information on molecular dynamics, conformational transitions, ligand binding, assigned chemical shifts, or other results from NMR spectroscopy. BMRB also provides resources for NMR studies of metabolites and other small molecules that are often macromolecular ligands and/or nonstandard residues. This chapter is directed to the structural biology community rather than the metabolomics and natural products community. Our goal is to describe various BMRB services offered to structural biology researchers and how they can be accessed and utilized. These services can be classified into four main groups: (1) data deposition, (2) data retrieval, (3) data analysis, and (4) services for NMR spectroscopists and software developers. The chapter also describes the NMR-STAR data format used by BMRB and the tools provided to facilitate its use. For programmers, BMRB offers an application programming interface (API) and libraries in the Python and R languages that enable users to develop their own BMRB-based tools for data analysis, visualization, and manipulation of NMR-STAR formatted files. BMRB also provides users with direct access tools through the NMRbox platform.
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http://dx.doi.org/10.1007/978-1-0716-0270-6_14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064287PMC
January 2021

Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy.

Hum Mol Genet 2020 02;29(3):444-458

Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1, Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan.

Inherited optic neuropathies are rare eye diseases of optic nerve dysfunction that present in various genetic forms. Previously, mutation in three genes encoding mitochondrial proteins has been implicated in autosomal recessive forms of optic atrophy that involve progressive degeneration of optic nerve and retinal ganglion cells (RGC). Using whole exome analysis, a novel double homozygous mutation p.L81R and pR212W in malonyl CoA-acyl carrier protein transacylase (MCAT), a mitochondrial protein involved in fatty acid biosynthesis, has now been identified as responsible for an autosomal recessive optic neuropathy from a Chinese consanguineous family. MCAT is expressed in RGC that are rich in mitochondria. The disease variants lead to structurally unstable MCAT protein with significantly reduced intracellular expression. RGC-specific knockdown of Mcat in mice, lead to an attenuated retinal neurofiber layer, that resembles the phenotype of optic neuropathy. These results indicated that MCAT plays an essential role in mitochondrial function and maintenance of RGC axons, while novel MCAT p.L81R and p.R212W mutations can lead to optic neuropathy.
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http://dx.doi.org/10.1093/hmg/ddz311DOI Listing
February 2020

Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies.

Sci Rep 2019 11 14;9(1):16851. Epub 2019 Nov 14.

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.

GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as "pathogenic", whereas the other five variants, which did not co-segregate with IRDs, were considered "non-pathogenic". Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.
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http://dx.doi.org/10.1038/s41598-019-52660-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856191PMC
November 2019

Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings.

Invest Ophthalmol Vis Sci 2019 11;60(14):4691-4700

Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Purpose: To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings.

Methods: Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed.

Results: The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed.

Conclusions: The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.
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http://dx.doi.org/10.1167/iovs.19-27486DOI Listing
November 2019

Novel homozygous in-frame deletion of gene causes golden appearance of fundus and reduced scotopic ERGs similar to that in Oguchi disease in Japanese family.

Ophthalmic Genet 2019 10 7;40(5):480-487. Epub 2019 Nov 7.

Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan.

: The gene encodes the alpha-subunit of transducin in rod photoreceptors and is an important part of the phototransduction cascade. Defects in are very rare but have been identified in autosomal dominant and recessive congenital stationary night blindness (CSNB) and autosomal recessive rod-cone dystrophy. The purpose of this study was to determine the phenotype-genotype relationship in a non-consanguineous Japanese family with a mutation.: Detailed ophthalmic examinations were performed on the patients and their family members. Whole exome sequencing (WES) was applied to the DNA obtained from the family members. Sanger sequencing and co-segregation analyses were performed to identify the most likely pathogenic variant.: Two female (13- and 11-years) and one male (15-years) patients from a family had night blindness from their childhood. The fundus had a mild golden appearance regardless of the state of light- or dark-adaptation. Electroretinographic (ERG) analyses showed that the scotopic a-wave was extinguished, and the mixed rod-cone responses were severely reduced with an electronegative form in patients. The shapes of the dark-adapted ERGs were similar to those recorded from patients with Oguchi disease. We identified a homozygous in-frame deletion c.818_820delAGA, p.Lys273del in the gene. Variants were verified by Sanger sequencing and co-segregated with the disease in five members of the family.: Our findings indicate that a recessive mutation found in this family could be the cause of the golden appearance of the fundus and negative ERGs with reduced a-waves, and nearly absent b-waves in the mixed rod-cone ERGs.
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http://dx.doi.org/10.1080/13816810.2019.1686159DOI Listing
October 2019

Autosomal dominant optic atrophy with gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort.

Mol Vis 2019 5;25:559-573. Epub 2019 Oct 5.

Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Purpose: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease).

Methods: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications-that is, with simple DOA-were compared to those of DOA-plus patients.

Results: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA.

Conclusions: All the patients with the DOA-plus phenotype carried one of the missense mutations in the gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications-such as auditory neuropathy, vestibular dysfunction, and ataxia-followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798706PMC
April 2020
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