143 results on '"Yoshitake, Kazutoshi"'
Search Results
102. Creation of a novel telomere-cutting endonuclease based on the EN domain of telomere-specific non-long terminal repeat retrotransposon, TRAS1
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Yoshitake Kazutoshi, Aoyagi Hideyuki, and Fujiwara Haruhiko
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Genetics ,QH426-470 - Abstract
Abstract Background The ends of chromosomes, termed telomeres consist of repetitive DNA. The telomeric sequences shorten with cell division and, when telomeres are critically abbreviated, cells stop proliferating. However, in cancer cells, by the expression of telomerase which elongates telomeres, the cells can continue proliferating. Many approaches for telomere shortening have been pursued in the past, but to our knowledge, cutting telomeres in vivo has not so far been demonstrated. In addition, there is lack of information on the cellular effects of telomere shortening in human cells. Results Here, we created novel chimeric endonucleases to cut telomeres by fusing the endonuclease domain (TRAS1EN) of the silkworm's telomere specific non-long terminal repeat retrotransposon TRAS1 to the human telomere-binding protein, TRF1. An in vitro assay demonstrated that the TRAS1EN-TRF1 chimeric endonucleases (T-EN and EN-T) cut the human (TTAGGG)n repeats specifically. The concentration of TRAS1EN-TRF1 chimeric endonucleases necessary for the cleavage of (TTAGGG)n repeats was about 40-fold lower than that of TRAS1EN alone. When TRAS1EN-TRF1 endonucleases were introduced into human U2OS cancer cells using adenovirus vectors, the enzymes localized at telomeres of nuclei, cleaved and shortened the telomeric DNA by double-strand breaks. When human U2OS and HFL-1 fibroblast cells were infected with EN-T recombinant adenovirus, their cellular proliferation was suppressed for about 2 weeks after infection. In contrast, the TRAS1EN mutant (H258A) chimeric endonuclease fused with TRF1 (ENmut-T) did not show the suppression effect. The EN-T recombinant adenovirus induced telomere shortening in U2OS cells, activated the p53-dependent pathway and caused the senescence associated cellular responses, while the ENmut-T construct did not show such effects. Conclusions A novel TRAS1EN-TRF1 chimeric endonuclease (EN-T) cuts the human telomeric repeats (TTAGGG)n specifically in vitro and in vivo. Thus, the chimeric endonuclease which is expressed from an adenoviral vector can suppress cell proliferation of cancer cells.
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- 2010
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103. 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.
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Fujinami, Kaoru, Oishi, Akio, Yang, Lizhu, Arno, Gavin, Pontikos, Nikolas, Yoshitake, Kazutoshi, Fujinami‐Yokokawa, Yu, Liu, Xiao, Hayashi, Takaaki, Katagiri, Satoshi, Mizobuchi, Kei, Mizota, Atsushi, Shinoda, Kei, Nakamura, Natsuko, Kurihara, Toshihide, Tsubota, Kazuo, Miyake, Yozo, Iwata, Takeshi, Tsujikawa, Akitaka, and Tsunoda, Kazushige
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- 2020
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104. Author response: Molecular basis of wax-based color change and UV reflection in dragonflies
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Futahashi, Ryo, primary, Yamahama, Yumi, additional, Kawaguchi, Migaku, additional, Mori, Naoki, additional, Ishii, Daisuke, additional, Okude, Genta, additional, Hirai, Yuji, additional, Kawahara-Miki, Ryouka, additional, Yoshitake, Kazutoshi, additional, Yajima, Shunsuke, additional, Hariyama, Takahiko, additional, and Fukatsu, Takema, additional
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- 2018
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105. Age-associated different transcriptome profiling in zebrafish and rat: insight into diversity of vertebrate aging
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Kijima, Yusuke, primary, Wantong, Wang, additional, Igarashi, Yoji, additional, Yoshitake, Kazutoshi, additional, Asakawa, Shuichi, additional, Suzuki, Yutaka, additional, Watabe, Shugo, additional, and Kinoshita, Shigeharu, additional
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- 2018
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106. Whole-Genome Sequencing of 84 Japanese Eels Reveals Evidence against Panmixia and Support for Sympatric Speciation
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Igarashi, Yoji, primary, Zhang, Hong, additional, Tan, Engkong, additional, Sekino, Masashi, additional, Yoshitake, Kazutoshi, additional, Kinoshita, Shigeharu, additional, Mitsuyama, Susumu, additional, Yoshinaga, Tatsuki, additional, Chow, Seinen, additional, Kurogi, Hiroaki, additional, Shinoda, Akira, additional, Han, Yu-San, additional, Wakiya, Ryoshiro, additional, Mochioka, Noritaka, additional, Yamamoto, Toshihiro, additional, Kuwada, Hiroshi, additional, Kaji, Yoshitsugu, additional, Suzuki, Yutaka, additional, Gojobori, Takashi, additional, Kobayashi, Takanori, additional, Saitoh, Kenji, additional, Watabe, Shugo, additional, and Asakawa, Shuichi, additional
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- 2018
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107. Autosomal dominant retinitis pigmentosa with macular involvement associated with a disease haplotype that included a novel PRPH2 variant (p.Cys250Gly)
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Katagiri, Satoshi, primary, Hayashi, Takaaki, additional, Mizobuchi, Kei, additional, Yoshitake, Kazutoshi, additional, Iwata, Takeshi, additional, and Nakano, Tadashi, additional
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- 2018
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108. Lactomycins A–C, Dephosphorylated Phoslactomycin Derivatives that Inhibit Cathepsin B, from the Marine-derived Streptomyces sp. ACT232
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Sun, Yi, primary, Carandang, Rogie, additional, Harada, Yuta, additional, Okada, Shigeru, additional, Yoshitake, Kazutoshi, additional, Asakawa, Shuichi, additional, Nogi, Yuichi, additional, Matsunaga, Shigeki, additional, and Takada, Kentaro, additional
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- 2018
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109. Designed hybrids facilitate efficient generation of high-resolution linkage maps
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Yoshitake, Kazutoshi, primary, Igarashi, Yoji, additional, Mizukoshi, Misaki, additional, Kinoshita, Shigeharu, additional, Mitsuyama, Susumu, additional, Suzuki, Yutaka, additional, Saito, Kazuyoshi, additional, Watabe, Shugo, additional, and Asakawa, Shuichi, additional
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- 2018
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110. Maser: one-stop platform for NGS big data from analysis to visualization
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Kinjo, Sonoko, primary, Monma, Norikazu, additional, Misu, Sadahiko, additional, Kitamura, Norikazu, additional, Imoto, Junichi, additional, Yoshitake, Kazutoshi, additional, Gojobori, Takashi, additional, and Ikeo, Kazuho, additional
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- 2018
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111. Whole-exome sequencing identifies a novel ALMS1 mutation (p.Q2051X) in two Japanese brothers with Alström syndrome
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Katagiri, Satoshi, Yoshitake, Kazutoshi, Akahori, Masakazu, Hayashi, Takaaki, Furuno, Masaaki, Nishino, Jo, Ikeo, Kazuho, Tsuneoka, Hiroshi, and Iwata, Takeshi
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Adult ,Male ,Heterozygote ,genetic structures ,Siblings ,Homozygote ,Proteins ,Cell Cycle Proteins ,Exons ,Sequence Analysis, DNA ,Middle Aged ,Pedigree ,Consanguinity ,Asian People ,Codon, Nonsense ,Humans ,Point Mutation ,Exome ,Female ,Alstrom Syndrome ,Research Article - Abstract
Purpose No mutations associated with Alström syndrome (AS), a rare autosomal recessive disease, have been reported in the Japanese population. The purpose of this study was to investigate the genetic and clinical features of two brothers with AS in a consanguineous Japanese family. Methods Whole-exome sequencing analysis was performed on two brothers with AS and their unaffected parents. We performed a complete ophthalmic examination, including decimal best-corrected visual acuity, slit-lamp and funduscopic examination, visual-field and color-vision testing, full-field electroretinography, and optical coherence tomography. Fasting blood tests and systemic examinations were also performed. Results A novel mutation (c.6151C>T in exon 8) in the Alström syndrome 1 (ALMS1) gene that causes a premature termination codon at amino acid 2051 (p.Q2051X), was identified in the homozygous state in the affected brothers and in the heterozygous state in the parents. The ophthalmologic findings for both brothers revealed infantile-onset severe retinal degeneration and visual impairment, marked macular thinning, and severe cataracts. Systemic findings showed hepatic dysfunction, hyperlipidemia, hypogonadism, short stature, and wide feet in both brothers, whereas hearing loss, renal failure, abnormal digits, history of developmental delay, scoliosis, hypertension, and alopecia were not observed in either brother. The older brother exhibited type 2 diabetic mellitus and obesity, whereas the younger brother had hyperinsulinemia and subclinical hypothyroidism. Conclusions A novel ALMS1 mutation was identified by using whole-exome sequencing analysis, which is useful not only to identify a disease causing mutation but also to exclude other gene mutations. Although characteristic ophthalmologic findings and most systemic findings were similar between the brothers, the brothers differed slightly in terms of glucose tolerance and thyroid function.
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- 2013
112. Collaborative environmental DNA sampling from petal surfaces of flowering cherry Cerasus ×- yedoensis 'Somei-yoshino' across the Japanese archipelago
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Ohta, Tazro, primary, Kawashima, Takeshi, additional, Shinozaki, Natsuko O., additional, Dobashi, Akito, additional, Hiraoka, Satoshi, additional, Hoshino, Tatsuhiko, additional, Kanno, Keiichi, additional, Kataoka, Takafumi, additional, Kawashima, Shuichi, additional, Matsui, Motomu, additional, Nemoto, Wataru, additional, Nishijima, Suguru, additional, Suganuma, Natsuki, additional, Suzuki, Haruo, additional, Taguchi, Y-h., additional, Takenaka, Yoichi, additional, Tanigawa, Yosuke, additional, Tsuneyoshi, Momoka, additional, Yoshitake, Kazutoshi, additional, Sato, Yukuto, additional, Yamashita, Riu, additional, Arakawa, Kazuharu, additional, and Iwasaki, Wataru, additional
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- 2017
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113. In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant
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Ueno, Shinji, primary, Nakanishi, Ayami, additional, Kominami, Taro, additional, Ito, Yasuki, additional, Hayashi, Takaaki, additional, Yoshitake, Kazutoshi, additional, Kawamura, Yuichi, additional, Tsunoda, Kazushige, additional, Iwata, Takeshi, additional, and Terasaki, Hiroko, additional
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- 2016
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114. CCT2 Mutations Evoke Leber Congenital Amaurosis due to Chaperone Complex Instability
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Minegishi, Yuriko, primary, Sheng, XunLun, additional, Yoshitake, Kazutoshi, additional, Sergeev, Yuri, additional, Iejima, Daisuke, additional, Shibagaki, Yoshio, additional, Monma, Norikazu, additional, Ikeo, Kazuho, additional, Furuno, Masaaki, additional, Zhuang, Wenjun, additional, Liu, Yani, additional, Rong, Weining, additional, Hattori, Seisuke, additional, and Iwata, Takeshi, additional
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- 2016
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115. NovelRP1L1Variants and Genotype–Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy
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Fujinami, Kaoru, primary, Kameya, Shuhei, additional, Kikuchi, Sachiko, additional, Ueno, Shinji, additional, Kondo, Mineo, additional, Hayashi, Takaaki, additional, Shinoda, Kei, additional, Machida, Shigeki, additional, Kuniyoshi, Kazuki, additional, Kawamura, Yuichi, additional, Akahori, Masakazu, additional, Yoshitake, Kazutoshi, additional, Katagiri, Satoshi, additional, Nakanishi, Ayami, additional, Sakuramoto, Hiroyuki, additional, Ozawa, Yoko, additional, Tsubota, Kazuo, additional, Yamaki, Kunihiko, additional, Mizota, Atsushi, additional, Terasaki, Hiroko, additional, Miyake, Yozo, additional, Iwata, Takeshi, additional, and Tsunoda, Kazushige, additional
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- 2016
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116. Identification of Novel Mutations in the LRR-Cap Domain ofC21orf2in Japanese Patients With Retinitis Pigmentosa and Cone–Rod Dystrophy
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Suga, Akiko, primary, Mizota, Atsushi, additional, Kato, Mitsuhiro, additional, Kuniyoshi, Kazuki, additional, Yoshitake, Kazutoshi, additional, Sultan, William, additional, Yamazaki, Masashi, additional, Shimomura, Yoshikazu, additional, Ikeo, Kazuho, additional, Tsunoda, Kazushige, additional, and Iwata, Takeshi, additional
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- 2016
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117. Correction to: Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.
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Mawatari, Go, Fujinami, Kaoru, Liu, Xiao, Yang, Lizhu, Fujinami-Yokokawa, Yu, Komori, Shiori, Ueno, Shinji, Terasaki, Hiroko, Katagiri, Satoshi, Hayashi, Takaaki, Kuniyoshi, Kazuki, Miyake, Yozo, Tsunoda, Kazushige, Yoshitake, Kazutoshi, Iwata, Takeshi, and Nao-i, Nobuhisa
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RETINAL diseases ,RETINITIS pigmentosa - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
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- 2020
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118. Autosomal dominant retinitis pigmentosa with macular involvement associated with a disease haplotype that included a novel <italic>PRPH2</italic> variant (p.Cys250Gly).
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Katagiri, Satoshi, Hayashi, Takaaki, Mizobuchi, Kei, Yoshitake, Kazutoshi, Iwata, Takeshi, and Nakano, Tadashi
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RETINITIS pigmentosa ,HAPLOTYPES ,CLINICAL trials ,BIOFLUORESCENCE ,ELECTRORETINOGRAPHY ,THERAPEUTICS - Abstract
Background : It is known thatPRPH2 variants appear to be rare causes of retinitis pigmentosa (RP) in the Japanese population. The purpose of this study was to describe clinical and genetic features in autosomal dominant RP (adRP) patients with a novel disease-causing variant in thePRHP2 gene.Materials and methods : A total of 57 unrelated Japanese probands with adRP were investigated in this study. Comprehensive ophthalmic examinations include fundus photography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, and electroretinography. Whole exome sequencing or Sanger sequencing for 25 targeted exons of multiple genes causing adRP was performed to identify disease-causing variants. Co-segregation and haplotype analyses were performed to determine a disease-causing gene variant and its haplotype.Results : Genetic analysis identified a novel heterozygousPRPH2 variant (c.748T>G, p.Cys250Gly) as disease causing in four probands from four families. The variant co-segregated with the RP phenotype in the eight affected patients in all families. At least three of the four families shared the same haplotype for the variant allele. Clinically, seven of the eight affected patients exhibited typical RP presentation, as well as variable macular involvement including cystoid macular change, vitelliform-like appearance, choroidal neovascularization, and macular atrophy.Conclusions : The same disease haplotype that included a novelPRPH2 variant (p.Cys250Gly) was identified in three of the four Japanese families with adRP, suggesting a founder effect. Our clinical findings indicate that adRP caused by the p.Cys250Gly variant may accompany macular involvement with high frequency. [ABSTRACT FROM AUTHOR]- Published
- 2018
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119. Variations in Physiology and Genomic Function of ProchlorococcusAcross the Eastern Indian Ocean
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Jiang, Siyu, Hashihama, Fuminori, Liu, Hongbin, Yoshitake, Kazutoshi, Takami, Hideto, Hamasaki, Koji, Ikhsani, Idha Yulia, Obata, Hajime, and Saito, Hiroaki
- Abstract
The widespread distribution of Prochlorococcuscan be attributed to the extensive genetic diversity that allows them to adapt to various oligotrophic environments. We investigated the adaptation of Prochlorococcusto nutrient environments in the surface eastern Indian Ocean (EIO, 16.5°N to 20°S, 88°E) in November 2018. The growth rate of the Prochlorococcuspopulation and its response to macronutrient enrichments (NH4+andPO43−${{\text{NH}}_{4}}^{+}\,\text{and}\,{{\text{PO}}_{4}}^{3-}$) and the abundance of functional gene modules related to nutrient utilization were examined by on‐deck incubation experiments and metagenomic analysis, respectively. Although the dissolved inorganic nitrogen was depleted (∼58 nM) and the Prochlorococcuspopulations were dominated by the high‐light‐adapted II ecotype, Prochlorococcuspopulations showed distinct physiological patterns, especially the response to macronutrient enrichments, indicating their adaptation to local nutrient environments. At the northernmost station in the Bay of Bengal, the significant increase in growth rate with macronutrient enrichments and the highest abundance of the phosphate starvation response two‐component regulatory system module indicated adaptation to phosphorus‐limited environments. In the southern EIO, the insignificant increase in growth rate with macronutrient enrichment and higher abundance of the iron complex transport system module suggested adaptation to iron‐limited environments. However, genomic characteristics are not always associated with physiological characteristics. The abundance of the nitrate/nitrite transport system module was higher in the southern EIO, where the growth of Prochlorococcusrelied on regenerated nitrogen sources as revealed by incubation experiments. These results reflected the complexity of Prochlorococcusadaptation especially in chronically oligotrophic environments, which was better revealed by combining physiological and genomic analyses. Prochlorococcusare the smallest but most abundant photosynthetic organisms on Earth. Their widespread distribution (40°N to 40°S) and dominance in global subtropical and tropical phytoplankton communities could be attributed to the extensive genetic diversity that allows them to adapt to various environments. Although the adaptation of Prochlorococcusto nutrient environments could be reflected by variation in the genome, this method sometimes masks the complexity of Prochlorococcusadaptation. In this study, we combined incubation experiments with metagenomic analysis to better understand Prochlorococcusadaptation in the eastern Indian Ocean, which is consistently nutrient‐depleted but has subtle variations in nutrient environments. The results showed that the Prochlorococcuspopulation had three distinct physiological patterns in the study area. In particular, the distinct response to the additional nutrients in incubation experiments indicated their specific adaptations to local nutrient environments. Furthermore, by considering the physiological characteristics with the spatially varied abundance of functional genes related to nutrient acquisition, it was revealed that Prochlorococcusgrowth was limited by different nutrients (nitrogen, phosphorus or iron) across the study area. Our results suggested the complexity of Prochlorococcusadaptation to oligotrophic environments, which can be elucidated by considering both physiological and genomic characteristics. Prochlorococcushad varied physiological and genomic characteristics as adaptations to nutrient environments in the eastern Indian OceanProchlorococcusadapted to phosphorus‐ and iron‐limited environments in the Bay of Bengal and southern eastern Indian Ocean, respectivelyThe adaptation of Prochlorococcuscould be complex and better revealed by conducting both the physiological and genomic analyses Prochlorococcushad varied physiological and genomic characteristics as adaptations to nutrient environments in the eastern Indian Ocean Prochlorococcusadapted to phosphorus‐ and iron‐limited environments in the Bay of Bengal and southern eastern Indian Ocean, respectively The adaptation of Prochlorococcuscould be complex and better revealed by conducting both the physiological and genomic analyses
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- 2023
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120. Congenital Achromatopsia and Macular Atrophy Caused by a Novel RecessivePDE6CMutation (p.E591K)
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Katagiri, Satoshi, primary, Hayashi, Takaaki, additional, Yoshitake, Kazutoshi, additional, Sergeev, Yuri, additional, Akahori, Masakazu, additional, Furuno, Masaaki, additional, Nishino, Jo, additional, Ikeo, Kazuho, additional, Tsunoda, Kazushige, additional, Tsuneoka, Hiroshi, additional, and Iwata, Takeshi, additional
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- 2015
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121. RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis
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Katagiri, Satoshi, primary, Hayashi, Takaaki, additional, Kondo, Mineo, additional, Tsukitome, Hideyuki, additional, Yoshitake, Kazutoshi, additional, Akahori, Masakazu, additional, Ikeo, Kazuho, additional, Tsuneoka, Hiroshi, additional, and Iwata, Takeshi, additional
- Published
- 2014
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122. Novel nonsense and splice site mutations in CRB1 gene in two Japanese patients with early-onset retinal dystrophy
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Kuniyoshi, Kazuki, primary, Ikeo, Kazuho, additional, Sakuramoto, Hiroyuki, additional, Furuno, Masaaki, additional, Yoshitake, Kazutoshi, additional, Hatsukawa, Yoshikazu, additional, Nakao, Akira, additional, Tsunoda, Kazushige, additional, Kusaka, Shunji, additional, Shimomura, Yoshikazu, additional, and Iwata, Takeshi, additional
- Published
- 2014
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123. Whole Exome Analysis Identifies Frequent CNGA1 Mutations in Japanese Population with Autosomal Recessive Retinitis Pigmentosa
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Katagiri, Satoshi, primary, Akahori, Masakazu, additional, Sergeev, Yuri, additional, Yoshitake, Kazutoshi, additional, Ikeo, Kazuho, additional, Furuno, Masaaki, additional, Hayashi, Takaaki, additional, Kondo, Mineo, additional, Ueno, Shinji, additional, Tsunoda, Kazushige, additional, Shinoda, Kei, additional, Kuniyoshi, Kazuki, additional, Tsurusaki, Yohinori, additional, Matsumoto, Naomichi, additional, Tsuneoka, Hiroshi, additional, and Iwata, Takeshi, additional
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- 2014
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124. Performance comparison of second- and third-generation sequencers using a bacterial genome with two chromosomes
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Miyamoto, Mari, primary, Motooka, Daisuke, additional, Gotoh, Kazuyoshi, additional, Imai, Takamasa, additional, Yoshitake, Kazutoshi, additional, Goto, Naohisa, additional, Iida, Tetsuya, additional, Yasunaga, Teruo, additional, Horii, Toshihiro, additional, Arakawa, Kazuharu, additional, Kasahara, Masahiro, additional, and Nakamura, Shota, additional
- Published
- 2014
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125. NovelC8orf37Mutations in Patients with Early-onset Retinal Dystrophy, Macular Atrophy, Cataracts, and High Myopia
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Katagiri, Satoshi, primary, Hayashi, Takaaki, additional, Yoshitake, Kazutoshi, additional, Akahori, Masakazu, additional, Ikeo, Kazuho, additional, Gekka, Tamaki, additional, Tsuneoka, Hiroshi, additional, and Iwata, Takeshi, additional
- Published
- 2014
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126. RHOMutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa
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Katagiri, Satoshi, primary, Hayashi, Takaaki, additional, Akahori, Masakazu, additional, Itabashi, Takeshi, additional, Nishino, Jo, additional, Yoshitake, Kazutoshi, additional, Furuno, Masaaki, additional, Ikeo, Kazuho, additional, Okada, Tetsuji, additional, Tsuneoka, Hiroshi, additional, and Iwata, Takeshi, additional
- Published
- 2014
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127. LRRTM4-C538Ynovel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells
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Kawamura, Yuichi, Suga, Akiko, Fujimaki, Takuro, Yoshitake, Kazutoshi, Tsunoda, Kazushige, Murakami, Akira, and Iwata, Takeshi
- Abstract
The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole-exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post-synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype–phenotype annotated database identified novel mutation in atypical adMD.
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- 2018
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128. RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis.
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Katagiri, Satoshi, Hayashi, Takaaki, Kondo, Mineo, Tsukitome, Hideyuki, Yoshitake, Kazutoshi, Akahori, Masakazu, Ikeo, Kazuho, Tsuneoka, Hiroshi, and Iwata, Takeshi
- Subjects
HYDROLASES ,RHODOPSIN ,CONGENITAL disorders ,BLINDNESS ,ELECTRORETINOGRAPHY - Abstract
Purpose: To investigate genetic and clinical features of patients with Leber congenital amaurosis (LCA) caused byRPE65mutations. Methods: Five Japanese families with LCA were recruited. We performed complete ophthalmic examinations, with optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Genetic analysis was performed with whole-exome sequencing analysis and Sanger sequencing. Results: We identifiedRPE65mutations in two unrelated LCA patients from two families. Case 1: A 5-month-old girl was diagnosed with LCA because of nystagmus, loss of vision and non-recordable ERG. She was the only one affected in her non-consanguineous family, and exhibited novel compound heterozygousRPE65mutations (c.177C>G, p.H59Q and c.183_184insT, p.D62X). Case 2: A 30-year-old woman, who had night blindness and poor ocular pursuit during the first year of life, exhibited severe retinal degeneration and non-recordable ERG. She was the only affected in her non-consanguineous family, and showed a homozygousRPE65mutation (c.1543C>T, p.R515W). Conclusions: By using whole-exome sequencing analysis, threeRPE65mutations were identified in two Japanese patients with LCA. This approach would be useful for identification of disease-causing mutations of LCA. [ABSTRACT FROM PUBLISHER]
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- 2016
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129. Novel C8orf37 Mutations in Patients with Early-onset Retinal Dystrophy, Macular Atrophy, Cataracts, and High Myopia.
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Katagiri, Satoshi, Hayashi, Takaaki, Yoshitake, Kazutoshi, Akahori, Masakazu, Ikeo, Kazuho, Gekka, Tamaki, Tsuneoka, Hiroshi, and Iwata, Takeshi
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GENETIC mutation ,RETINAL degeneration ,ATROPHY ,CATARACT ,MYOPIA ,GENETICS - Abstract
Purpose: More than 50 genes are reported as causative genes of autosomal recessive (ar) retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). It is challenging to identify causative mutations for arRP and arCRD. The purpose of the present study was to investigate clinical and genetic features of two siblings with early-onset retinal dystrophy. Methods: Whole-exome sequencing was conducted for the two affected siblings and their unaffected brother and mother from a Japanese family. We performed complete ophthalmic examinations, including visual acuity, funduscopy, visual-field testing, electroretinography and optical coherence tomography. Results: Whole-exome sequencing analysis identified novel compound heterozygous mutations, a splice site mutation (c.374 + 2T > C in intron 4) and a deletion mutation (c.575delC [p.T192MfsX28] in exon 6) of chromosome 8 open reading frame 37 (C8orf37) gene, which encodes a ciliary protein, in both patients. The mother carried the truncating mutation, and the brother carried neither mutation. Ophthalmic examinations revealed diffuse retinal degeneration, macular atrophy, non-recordable electroretinography responses, cataracts, and high myopia in both patients, who could not be diagnosed with either RP or CRD because of the severe retinal degeneration and early onset disease. Longitudinal follow-up of the patients revealed highly progressive retinal degeneration, macular atrophy, and visual field loss. Conclusions: RecessiveC8orf37mutations have been identified in early to adolescent-onset arRP and arCRD with macular involvement. Our study identified two novel truncating mutations of theC8orf37gene in siblings with early-onset retinal dystrophy, macular atrophy, cataracts, and high myopia. [ABSTRACT FROM PUBLISHER]
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- 2016
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130. Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.
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Mawatari, Go, Fujinami, Kaoru, Liu, Xiao, Yang, Lizhu, Yokokawa, Yu-Fujinami, Komori, Shiori, Ueno, Shinji, Terasaki, Hiroko, Katagiri, Satoshi, Hayashi, Takaaki, Kuniyoshi, Kazuki, Miyake, Yozo, Tsunoda, Kazushige, Yoshitake, Kazutoshi, Iwata, Takeshi, and Nao-i, Nobuhisa
- Subjects
RETINITIS pigmentosa ,OPHTHALMOLOGY ,GUANOSINE triphosphatase ,PHOTORECEPTORS ,CELL division - Abstract
Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of X-linked inherited retinal disorder (IRD). We herein describe the clinical and genetic features of 14 patients from 13 Japanese families harboring RPGR variants in a nationwide cohort. Comprehensive ophthalmological examinations were performed to classify the patients into one of the phenotype subgroups: retinitis pigmentosa (RP) and cone rod dystrophy (CORD). The mean age of onset/at examination was 13.8/38.1 years (range, 0–50/11–72), respectively. The mean visual acuity in the right/left eye was 0.43/0.43 (range, 0.1–1.7/−0.08–1.52) LogMAR unit. Eight patients had RP, and six had CORD. Whole-exome sequencing with target analyses identified 13 RPGR variants in 730 families with IRD, including 8 novel variants. An association between the phenotype subgroup and the position of variants (cutoff of amino acid 950) was revealed. To conclude, the clinical and genetic spectrum of RPGR-associated retinal disorder was first illustrated in a Japanese population, with a high proportion of novel variants. These results suggest the distinct genetic background of RPGR in the Japanese population, in which the genotype–phenotype association was affirmed. This evidence should be helpful monitoring and counseling patients and in selecting patients for future therapeutic trials. Retinal disorders: Seeing new patterns New mutations that cause inherited retinal disorders (IRD) such as retinitis pigmentosa have been identified in Japanese patients. IRD, which affect the light-sensing rods and cones of the eye, often appear in childhood, and may cause blindness by middle age. IRD have been traced to mutations of the retinal development gene RPGR, but have mainly been studied in European populations. Go Mawatari and coworkers studied the genetics of IRD in 14 Japanese patients, and searched genetic data collected during the past decade from over 1000 Japanese patients with IRD registered in the Japan Eye Genetics Consortium database. They found eight novel RPGR mutations and noticed that mutations in different parts of the gene cause different types of IRD. These data will help in diagnosis and counselling of patients with these rare eye disorders. [ABSTRACT FROM AUTHOR]
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- 2019
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131. Dimerization-based homogeneous fluorosensor proteins for the detection of specific dsDNA
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Yoshitake, Kazutoshi, Waki, Shoko, and Ueda, Hiroshi
- Abstract
While there are many hybridization-based DNA sensors, few can detect native double-stranded DNA (dsDNA), which is most commonly found in physiological conditions. Here we made novel fluorosensor proteins comprised of a pair of two zinc fingers with an N-terminal dimerization motif and a C-terminal GFP variant to detect specific dsDNA sequence in a homogeneous solution. When a pair of purified zinc finger-GFP colour variant proteins (Zif12-eCFP, Zif12-eYFP) were mixed and added with specific dsDNA with 12 bp inverted repeat sequence, fluorescence spectra of the solution showed significant concentration-dependent enhancement of fluorescence resonance energy transfer (FRET), with the detection limit of ∼10 nM. No significant change in FRET was observed upon addition of dsDNA with non-specific sequence, indicating dsDNA-dependent dimerization of the two proteins. This dimerization-based dsDNA sensors will have a range of applications where conventional hybridiza-tion-based assay is difficult.
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- 2007
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132. Fluorosensor proteins to detect specific DNA sequences in living bacteria
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Waki, Shoko, Yoshitake, Kazutoshi, Iwasaki, Ryohei, and Ueda, Hiroshi
- Abstract
While there are many hybridization-based DNA sensors, few of them can detect native double-stranded DNA, which is most commonly found in physiological conditions. Here we made novel fluorosensor proteins comprised of a pair of two zinc fingers tethered with an N-terminal dimerization motif and a C-terminal yellow fluorescent protein fragment (split eYFP) to detect specific DNA sequence in a living bacteria. When E. coli Top10 cells harboring the plasmid encoding the fusion proteins and a test plasmid encoding target DNA sequence were induced for the protein expression, significant increase in fluorescence was observed, compared with the strain harboring a test plasmid without target DNA sequence.
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- 2007
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133. Francisellosis of Yesso scallops Mizuhopecten yessoensis in Japan is caused by a novel type of Francisella halioticida.
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Kawahara M, Yoshitake K, Yoshinaga T, and Itoh N
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- Animals, Japan epidemiology, Francisella genetics, Gastropoda, Pectinidae
- Abstract
Francisella halioticida, the causative agent of francisellosis of the giant abalone Haliotis gigantea, has also been isolated from Yesso scallops Mizuhopecten yessoensis, which presented with orange/pinkish lesions in the adductor muscle and experienced high mortality. However, it is not clear whether the F. halioticida isolated from the giant abalone and Yesso scallops are phenotypically and genetically identical to each other. The present study revealed that isolates from the giant abalone and Yesso scallops were phenotypically different, with slower growth in modified eugon broth and a lack of prolyl aminopeptidase and phenylalanine aminopeptidase in Yesso scallop isolates. Additionally, we found that 3 of 8 housekeeping genes were different between them. Based on these phenotypic and genetic differences, we propose that F. halioticida isolated from Yesso scallops in Japan be designated as the 'J-scallop type' to distinguish it from strains from abalone ('abalone type'). Whole-genome sequencing analysis of a strain belonging to the J-scallop type showed that the overall similarity between the J-scallop and abalone type strains was estimated to be 99.84%. In accordance with a lack of prolyl aminopeptidase activity, in general, all of the J-scallop type strains examined have a 1 bp deletion in the responsible gene encoding prolyl aminopeptidase. This deletion was confirmed in all F. halioticida in diseased Yesso scallops examined, suggesting that in Japan, francisellosis of Yesso scallops is caused by a novel type of F. halioticida and not by the abalone type.
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- 2021
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134. Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D -Associated Retinal Disorder.
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Liu X, Fujinami K, Kuniyoshi K, Kondo M, Ueno S, Hayashi T, Mochizuki K, Kameya S, Yang L, Fujinami-Yokokawa Y, Arno G, Pontikos N, Sakuramoto H, Kominami T, Terasaki H, Katagiri S, Mizobuchi K, Nakamura N, Yoshitake K, Miyake Y, Li S, Kurihara T, Tsubota K, Iwata T, and Tsunoda K
- Subjects
- Cohort Studies, Asia, Eastern, Humans, Japan epidemiology, Guanylate Cyclase genetics, Receptors, Cell Surface genetics
- Abstract
Purpose: To determine the clinical and genetic characteristics of patients with GUCY2D -associated retinal disorder ( GUCY2D -RD)., Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D 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 GUCY2D 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 GUCY2D -RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D -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., Competing Interests: Disclosure: X. Liu, None; K. Fujinami, Astellas Pharma Inc. (C, F), Kubota Pharmaceutical Holdings Co. Ltd (C, F), Acucela Inc. (C, F), Novartis AG (C), Janssen Pharmaceutical K.K. (C), NightStar (C, F), SANTEN Company Limited (F), Foundation Fighting Blindness (F), Foundation Fighting Blindness Clinical Research Institute (F), Japanese Ophthalmology Society (F), Japan Retinitis Pigmentosa Society (F); K. Kuniyoshi, None; M. Kondo, None; S. Ueno, None; T. Hayashi, None; K. Mochizuki, None; S. Kameya, None; L. Yang, None; Y. Fujinami-Yokokawa, None; G. Arno, None; N. Pontikos, None; H. Sakuramoto, None; T. Kominami, None; H. Terasaki, None; S. Katagiri, None; K. Mizobuchi, None; N. Nakamura, None; K. Yoshitake, None; Y. Miyake, None; S. Li, None; T. Kurihara, Tsubota Laboratory, Inc. (F), Fuji Xerox Co., Ltd. (F), Kirin Company, Ltd. (F), Kowa Company, Ltd. (F), Novartis Pharmaceuticals (F), Santen Pharmaceutical Co., Ltd. (F), ROHTO Pharmaceutical Co., Ltd. (F); K. Tsubota, None; T. Iwata, None; K. Tsunoda, None, (Copyright 2020 The Authors.)
- Published
- 2020
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135. Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency.
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Yang L, Fujinami K, Ueno S, Kuniyoshi K, Hayashi T, Kondo M, Mizota A, Naoi N, Shinoda K, Kameya S, Fujinami-Yokokawa Y, Liu X, Arno G, Pontikos N, Kominami T, Terasaki H, Sakuramoto H, Katagiri S, Mizobuchi K, Nakamura N, Mawatari G, Kurihara T, Tsubota K, Miyake Y, Yoshitake K, Iwata T, and Tsunoda K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Asian People genetics, Child, Cohort Studies, Cone-Rod Dystrophies genetics, Female, Gene Frequency, Genes, Recessive, Genetic Association Studies, Genetic Variation, Humans, Japan, Leber Congenital Amaurosis genetics, Male, Middle Aged, Retinitis Pigmentosa genetics, Exome Sequencing, Young Adult, Eye Diseases, Hereditary genetics, Eye Proteins genetics, Mutation, Retinal Diseases genetics
- Abstract
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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- 2020
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136. Late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration.
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Tsunoda K, Fujinami K, Yoshitake K, and Iwata T
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- Aged, Dark Adaptation physiology, Electroretinography, Female, Humans, Late Onset Disorders genetics, Late Onset Disorders physiopathology, Macular Degeneration genetics, Macular Degeneration physiopathology, Male, Middle Aged, Night Blindness genetics, Night Blindness physiopathology, Night Vision physiology, Ophthalmoscopy, Retina physiopathology, Tomography, Optical Coherence, Visual Fields physiology, Exome Sequencing, Late Onset Disorders diagnosis, Macular Degeneration diagnosis, Night Blindness diagnosis, Retina abnormalities
- Abstract
Purpose: To report the clinical and genetic characteristics of 6 cases with late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration., Methods: Clinical and genetic data were collected from 6 independent patients who complained of night blindness in their fifth to eighth decade of life. The ophthalmological examinations included ophthalmoscopy, fundus autofluorescence (FAF), and full-field electroretinography (ERG). Whole exome sequencing with target gene analysis was performed to determine the causative genes and variants., Results: All of the patients first complained of night blindness at the ages of 40-71 years. Funduscopic examinations demonstrated white or atrophic flecks scattered in the posterior pole and peripheral retina bilaterally. FAF showed patchy hypo-autofluorescence spots in the posterior pole similar to that of the trickling type of age-related macular degeneration (AMD). The region of abnormal FAF rapidly expanded with age, and one eye developed a choroidal neovascularization. The full-field scotopic ERGs with 20 min of dark adaptation were severely reduced or extinguished in all cases. There was partial recovery of the ERGs after 180 min of dark adaptation. The cone ERGs were reduced in all cases. Whole exome sequencing revealed no pathogenic variants of 301 retinal disease-associated genes., Conclusions: The six cases had some common features with the flecked retina syndrome, familial drusen, and late-onset retinal degeneration although none had pathogenic variants causative for these disorders. These cases may represent a subset of severe trickling AMD or a new clinical entity of acquired pan-retinal visual cycle deficiency of unknown etiology.
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- 2019
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137. HaCeD-Seq: a Novel Method for Reliable and Easy Estimation About the Fish Population Using Haplotype Count from eDNA.
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Yoshitake K, Yoshinaga T, Tanaka C, Mizusawa N, Reza MS, Tsujimoto A, Kobayashi T, and Watabe S
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- Anguilla classification, Animals, Aquaculture methods, Environmental Monitoring methods, Water analysis, Anguilla genetics, DNA, Mitochondrial analysis, Haplotypes
- Abstract
It is common to count the numbers of specified fish in the field after speciation of captured fish according to their morphology and to subject these counts to appropriate statistical analyses. In recent years, a non-invasive method to estimate the abundance of a particular fish species using environmental DNA (eDNA) has been developed. However, it is still difficult to determine accurate numbers of fish species using such method. We predict that the estimation of individuals of certain fish species in the field is more accurate and easier by using haplotypes of DNA in the fast evolutionary region. Therefore, we focused on the regulatory region (D-loop) in mitochondrial DNA, which is known to have a high genetic variation at the intraspecific level of the targeting eel. We investigated haplotype diversity in eel at first and then determined the number of D-loop haplotypes contained in their exfoliated cells in breeding water. Finally, we developed a novel analytical method, HaCeD-Seq, to estimate the number of individuals based on the abovementioned data.
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- 2019
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138. Phenotypical Characteristics of POC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance.
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Kameya S, Fujinami K, Ueno S, Hayashi T, Kuniyoshi K, Ideta R, Kikuchi S, Kubota D, Yoshitake K, Katagiri S, Sakuramoto H, Kominami T, Terasaki H, Yang L, Fujinami-Yokokawa Y, Liu X, Arno G, Pontikos N, Miyake Y, Iwata T, and Tsunoda K
- Subjects
- Adult, Aged, Asian People genetics, Cohort Studies, Color Vision Defects diagnosis, Color Vision Defects physiopathology, Cone Dystrophy diagnosis, Cone Dystrophy physiopathology, Electroretinography, Female, Fluorescein Angiography, Humans, Japan epidemiology, Male, Middle Aged, Pedigree, Phenotype, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa genetics, Retinitis Pigmentosa physiopathology, Tomography, Optical Coherence, Visual Acuity physiology, Visual Field Tests, Visual Fields physiology, Exome Sequencing, Young Adult, Cell Cycle Proteins genetics, Color Vision Defects genetics, Cone Dystrophy genetics, Mutation
- Abstract
Purpose: Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC)., Methods: Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed., Results: There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from -0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases., Conclusions: Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.
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- 2019
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139. Novel biallelic loss-of-function KCNV2 variants in cone dystrophy with supernormal rod responses.
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Kutsuma T, Katagiri S, Hayashi T, Yoshitake K, Iejima D, Gekka T, Kohzaki K, Mizobuchi K, Baba Y, Terauchi R, Matsuura T, Ueno S, Iwata T, and Nakano T
- Subjects
- Adult, Electroretinography, Female, Follow-Up Studies, Humans, Ophthalmoscopy, Pedigree, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa physiopathology, Retrospective Studies, Tomography, Optical Coherence, Visual Fields physiology, Exome Sequencing, Potassium Channels, Voltage-Gated genetics, Retinal Rod Photoreceptor Cells physiology, Retinitis Pigmentosa genetics
- Abstract
Purpose: To report clinical and genetic features including long-term full-field electroretinography (FF-ERG) findings of a patient with cone dystrophy with supernormal rod responses (CDSRR)., Methods: Ophthalmological medical records including FF-ERG were retrospectively reviewed. Genetic analysis using whole-exome sequencing (WES) was performed. Identified KCNV2 variants were confirmed by Sanger sequencing., Results: A 30-year-old female patient was referred to our hospital for assessment of decreased vision from childhood. Funduscopy showed macular atrophy in both eyes. FF-ERG showed decreased amplitudes and delayed peak time of b-waves for dark-adapted (DA) 0.01 ERG, increased b/a-wave ratio with a slightly diminished a-wave for DA 3.0 and DA 25.7 ERG, residual a-waves and almost extinguished b-waves for light-adapted (LA) 3.0 ERG, and extremely diminished amplitudes in LA 30-Hz flicker responses. At 45 years of age, funduscopy showed progressive macular atrophy, whereas the responses for her FF-ERG remained unchanged compared to those observed at 30 years of age. WES identified the compound heterozygous KCNV2 variants (p.W67X and p.D174GfsX198) in the patient. These variants have previously been unreported as pathogenic variants. Each parent had one of the variants. Subsequently, the patient was finally diagnosed with CDSRR with the novel compound heterozygous KCNV2 variants., Conclusions: Biallelic loss-of-function KCNV2 variants (p.W67X and p.D174GfsX198) were identified as the cause of CDSRR. Long-term FF-ERG findings demonstrated there were no ERG changes during 15 years of observation, indicating that there was no evidence of progressive peripheral retinal dysfunction, in spite of worsening macular atrophy.
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- 2019
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140. Clinical findings of end-stage retinitis pigmentosa with a homozygous PDE6A variant (p.R653X).
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Mizobuchi K, Katagiri S, Hayashi T, Yoshitake K, Fujinami K, Kuniyoshi K, Mishima R, Tsunoda K, Iwata T, and Nakano T
- Abstract
Purpose: To report clinical and genetic features of a Japanese patient with end-stage retinitis pigmentosa (RP) caused by a homozygous PDE6A variant., Methods: We performed comprehensive ophthalmic examinations. Whole exome sequencing analysis was used to investigate the RP patient with parental consanguinity. The pedigree included 4 RP patients in the two generations, which suggests presumed pseudo-autosomal dominant inheritance., Results: A PDE6A variant (p.R653X) was identified to be homozygous and disease-causing in the patient. Homozygosity mapping revealed the homozygous region including the variant and confirmation of autosomal recessive inheritance. The patient reported night blindness at 4 years of age and exhibited typical RP fundus appearance with macula involvement during the follow-up period from at the age of 52-69 years. At the age of 52, the patient exhibited a loss of visual acuity and had severely constricted visual fields, with a further gradual deterioration of her vision until she was 69 years old. At the age of 69, funduscopy showed severe chorioretinal degeneration in the area from the posterior pole to the peripheral retina., Conclusions and Importance: This is the first report that the PDE6A variant (p.R653X) has been identified as one of the causes of autosomal recessive RP in the Japanese population. Longitudinal natural history/end-stage findings demonstrated early-onset and a severe RP phenotype with macula involvement when the patient was in her 50s and severe chorioretinal degenerations in her late 60s.
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- 2018
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141. Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy.
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Fujinami K, Kameya S, Kikuchi S, Ueno S, Kondo M, Hayashi T, Shinoda K, Machida S, Kuniyoshi K, Kawamura Y, Akahori M, Yoshitake K, Katagiri S, Nakanishi A, Sakuramoto H, Ozawa Y, Tsubota K, Yamaki K, Mizota A, Terasaki H, Miyake Y, Iwata T, and Tsunoda K
- Subjects
- Adolescent, Adult, Aged, DNA Mutational Analysis, Electroretinography, Eye Proteins metabolism, Female, Fluorescein Angiography, Follow-Up Studies, Fundus Oculi, Genotype, Humans, Incidence, Japan epidemiology, Macular Degeneration epidemiology, Macular Degeneration metabolism, Male, Middle Aged, Pedigree, Phenotype, Retina metabolism, Tomography, Optical Coherence, Visual Acuity, Young Adult, DNA genetics, Eye Proteins genetics, Macular Degeneration genetics, Mutation, Retina pathology
- Abstract
Purpose: To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study., Methods: Twenty-three patients from 21 families with clinically diagnosed OMD were studied at 10 institutions throughout Japan. Ophthalmologic examinations including spectral-domain optic coherence tomography were performed. Patients were classified into two phenotype groups: a classical group having both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors, and a nonclassical group lacking at least one of these two features. Whole-exome sequencing, direct sequencing, and in silico molecular analysis were performed to detect the pathogenic RP1L1 variants. Statistical associations between the phenotype and genotypes based on the presence of pathogenic RP1L1 variants were investigated., Results: There were 12 families with the classical findings and 9 families with the nonclassical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three reported variants, namely, p.R45W, p.S1199C, and p.G1200A, and six novel variants, p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, and p.V1201G. The pathogenic missense variants in seven families (33%) were located between amino acid numbers 1196 and 1201. A significant association was found between the photoreceptor microstructural phenotypes and molecular genotypes., Conclusions: The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyake's disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.
- Published
- 2016
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142. Identification of Novel Mutations in the LRR-Cap Domain of C21orf2 in Japanese Patients With Retinitis Pigmentosa and Cone-Rod Dystrophy.
- Author
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Suga A, Mizota A, Kato M, Kuniyoshi K, Yoshitake K, Sultan W, Yamazaki M, Shimomura Y, Ikeo K, Tsunoda K, and Iwata T
- Subjects
- Animals, Blotting, Western, Cells, Cultured, Child, Preschool, Cone-Rod Dystrophies epidemiology, Cone-Rod Dystrophies metabolism, Cytoskeletal Proteins, DNA Mutational Analysis, Exome, Female, Genes, Recessive, Homozygote, Humans, Japan epidemiology, Male, Mice, Middle Aged, Pedigree, Prevalence, Proteins metabolism, Retinitis Pigmentosa epidemiology, Retinitis Pigmentosa metabolism, Reverse Transcriptase Polymerase Chain Reaction, Cone-Rod Dystrophies genetics, DNA genetics, Mutation, Missense, Proteins genetics, Retinitis Pigmentosa genetics
- Abstract
Purpose: C21orf2 encodes a ciliary protein related to syndromic and nonsyndromic retinal degeneration. The purpose of this study was to identify novel mutations of C21orf2 associated with syndromic autosomal recessive retinitis pigmentosa (arRP) and autosomal recessive cone-rod dystrophy (arCRD) by using whole exome sequencing of a Japanese cohort., Methods: Whole exome sequencing was performed on DNA from affected and healthy members from 147 families with retinal degenerations. Identified nonsense and missense mutations were further restricted by using the reported single nucleotide variation frequencies and inherited patterns. The effect of the mutations was examined by in vitro assays., Results: Novel mutations in C21orf2 were found in Japanese patients with arRP with skeletal defects or arCRD. Compound heterozygous mutations, from one family (p.V111M and p.Y107H), and a homozygous mutation, from another family (p.Y107C), were all located in the leucine-rich repeat C-terminal domain required for protein stabilization. C21orf2 was expressed in the retina through the developing to the mature stage, and the protein localized to the photoreceptor cilia in the adult retina. In vitro expression showed reduced levels and affected localizations of mutated protein products compared to the wild type., Conclusions: The identified C21orf2 mutations decreased protein stability and affected cytoplasmic localization of C21orf2. Since C21orf2 was required for ciliogenesis, our data suggested that reduced levels of functional C21orf2 induced photoreceptor degradation through abnormal cilia formation, leading to arRP or arCRD in the retina.
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- 2016
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143. RHO Mutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa.
- Author
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Katagiri S, Hayashi T, Akahori M, Itabashi T, Nishino J, Yoshitake K, Furuno M, Ikeo K, Okada T, Tsuneoka H, and Iwata T
- Abstract
Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP). Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling.
- Published
- 2014
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