AOによる遺伝性網膜疾患超早期診断補助法の開発とAOデータベースの作成

• Project/Area Number: 19K09940
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Nippon Medical School
• Principal Investigator: 亀谷 修平 日本医科大学, 医学部, 准教授 (30302269)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Discontinued (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: HK1 / MIDD / 補償光学眼底カメラ / AO / POC1B / GNAT1 / GUCY2D / DRAM2 / エクソーム

Outline of Research at the Start

本研究の目的は補償光学（AO）眼底カメラによる遺伝性網膜疾患の超早期診断補助法の開発と遺伝性網膜疾患の治療効果判定のためのAO正常眼データベースを作成することである。
今後、国内でも遺伝子治療研究がスタートしていくものと考えられるが、その治療効果判定には微細な変化を検出できる手法の確立が必須である。補償光学眼底カメラは超高解像度で、網膜視細胞や神経細胞を観察可能な装置である。遺伝性網膜疾患の超早期診断や個々の疾患の特徴の検出に有用であることが多数の論文にて示されている。本研究は遺伝子治療の進歩のために有意義で、日本発の遺伝子治療研究に付加価値を付与するものと考えている。

Outline of Annual Research Achievements

エクソーム解析を用いて、網膜視神経変性疾患を引き起こす多数の遺伝子の解析を行い論文として報告した。解析を行った遺伝子はRP1L1遺伝子、POC1B遺伝子、OPA1遺伝子、GNAT1遺伝子、GUCY2D遺伝子、NOTCH2NLC遺伝子、DRAM2遺伝子、EYS遺伝子、CRX遺伝子、HK1遺伝子、RP2遺伝子、CHM遺伝子、PDE6A遺伝子、ミトコンドリア遺伝子などである。これらのうちHK1遺伝子の異常によって生じる常染色体優性網膜色素変性症(Autosomal dominant retinitis pigmentosa; adRP)に関しては、補償光学眼底カメラによる視細胞変性の過程を、細胞レベルで詳細に行って報告した。HK1遺伝子異常による網膜変性では視細胞の変性は緩徐で有り、20歳程度の患者で黄斑周囲2度から8度の部位での視細胞は正常者の半数以下に減少しているものの視力は（1.0）とほぼ正常な視機能を維持できることが分かった。40歳程度では周辺視細胞の変性が著しく、また黄斑周囲2度から8度の視細胞は測定困難となるが、その状態でも黄斑中心の機能は維持され視力に関しては（1.0）と良好に維持されることが分かった。また、ミトコンドリア遺伝子m.3243A>G変異によっておこる、Maternally inherited diabetes and deafness (MIDD)における黄斑変性についても、補償光学眼底カメラによる黄斑部視細胞変性の解析を行った。MIDDによる黄斑変性では、AOではRPEと脈絡膜に明らかな萎縮のない中心窩においても明らかな錐体細胞の密度の低下を認めた。この解析により、MIDDでは中心窩の視細胞の変性がRPEの変性より先に生じている可能性が示唆された。

Research Products

• [Journal Article] Multimodal imaging analysis of macular dystrophy in patient with maternally inherited diabetes and deafness (MIDD) with m.3243A>G mutation (2021)
  • Author(s): Oishi Noriko、Kubota Daiki、Nakamoto Kenji、Takeda Yukito、Hayashi Mika、Gocho Kiyoko、Yamaki Kunihiko、Igarashi Tsutomu、Takahashi Hiroshi、Kameya Shuhei
  • Journal Title: Ophthalmic Genetics Volume: 41 Issue: 3 Pages: 1-8
  • DOI: 10.1080/13816810.2021.1881978
  • Peer Reviewed / Open Access
• [Journal Article] A new PDE6A missense variant p.Arg544Gln in rod?cone dystrophy (2021)
  • Author(s): Hayashi Takaaki、Mizobuchi Kei、Kameya Shuhei、Yoshitake Kazutoshi、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Documenta Ophthalmologica Volume: online ahead Issue: 1 Pages: 107-114
  • DOI: 10.1007/s10633-021-09826-y
  • Peer Reviewed
• [Journal Article] Novel <i>GUCY2D</i> Variant (E843Q) at Mutation Hotspot Associated with Macular Dystrophy in a Japanese Patient (2020)
  • Author(s): Takeda Yukito、Kubota Daiki、Oishi Noriko、Maruyama Kaori、Gocho Kiyoko、Yamaki Kunihiko、Igarashi Tsutomu、Takahashi Hiroshi、Kameya Shuhei
  • Journal Title: Journal of Nippon Medical School Volume: 87 Issue: 2 Pages: 92-99
  • DOI: 10.1272/jnms.JNMS.2020_87-207
  • NAID: 130007843314
  • ISSN: 1345-4676, 1347-3409
  • Year and Date: 2020-04-15
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous GGC repeat expansion of NOTCH2NLC in a patient with neuronal intranuclear inclusion disease and progressive retinal dystrophy (2020)
  • Author(s): Hayashi Takaaki、Katagiri Satoshi、Mizobuchi Kei、Yoshitake Kazutoshi、Kameya Shuhei、Matsuura Tomokazu、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Ophthalmic Genetics Volume: 41 Issue: 1 Pages: 93-95
  • DOI: 10.1080/13816810.2020.1723119
  • Peer Reviewed
• [Journal Article] Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy (2020)
  • Author(s): Kuniyoshi Kazuki、Hayashi Takaaki、Kameya Shuhei、Katagiri Satoshi、Mizobuchi Kei、Tachibana Toshiaki、Kubota Daiki、Sakuramoto Hiroyuki、Tsunoda Kazushige、Fujinami Kaoru、Yoshitake Kazutoshi、Iwata Takeshi、Nakano Tadashi、Kusaka Shunji
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 4 Pages: 1331-1331
  • DOI: 10.3390/ijms21041331
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency. (2020)
  • Author(s): 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, Tsunoda K; JEGC study group.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-020-62119-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association (2020)
  • Author(s): Fujinami-Yokokawa Y, Fujinami K, Kuniyoshi K, Hayashi T, Ueno S, Mizota A, Shinoda K, Arno G, Pontikos N, Yang L, Liu X, Sakuramoto H, Katagiri S, Mizobuchi K, Kominami T, Terasaki H, Nakamura N, Kameya S, Yoshitake K, Miyake Y, Kurihara T, Tsubota K, Miyata H, Iwata T, Tsunoda K; Japan Eye Genetics Consortium.
  • Journal Title: Sci Rep Volume: 12 Issue: 1 Pages: 9531-9531
  • DOI: 10.1038/s41598-020-65737-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tyrosine triple mutated AAV2-BDNF gene therapy in an inner retinal injury model induced by intravitreal injection of N-methyl-D-aspartate (NMDA) (2020)
  • Author(s): Asaka Lee Shiozawa, Tsutomu Igarashi, Maika Kobayashi, Kenji Nakamoto, Shuhei Kameya, Shigeto Fujishita, Hiroshi Takahashi, Takashi Okada
  • Journal Title: Molecular Vision Volume: 26 Pages: 409-422
  • Peer Reviewed / Open Access
• [Journal Article] High-resolution photoreceptor imaging analysis of patients with autosomal dominant retinitis pigmentosa (adRP) caused by HK1 mutation (2020)
  • Author(s): Kubota Daiki、Matsumoto Kaori、Hayashi Mika、Oishi Noriko、Gocho Kiyoko、Yamaki Kunihiko、Kobayakawa Shinichiro、Igarashi Tsutomu、Takahashi Hiroshi、Kameya Shuhei
  • Journal Title: Ophthalmic Genetics Volume: 41 Issue: 6 Pages: 629-638
  • DOI: 10.1080/13816810.2020.1810284
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Characteristics of 15 Affected Patients From 12 Japanese Families with GUCY2D-Associated Retinal Disorder (2020)
  • Author(s): 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, Tsunoda K; Japan Eye Genetics Consortium
  • Journal Title: Transl Vis Sci Technol Volume: 11 Issue: 6 Pages: 2-2
  • DOI: 10.1167/tvst.9.6.2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association. (2020)
  • Author(s): Fujinami K, Liu X, Ueno S, Mizota A, Shinoda K, Kuniyoshi K, Fujinami-Yokokawa Y, Yang L, Arno G, Pontikos N, Kameya S, Kominami T, Terasaki H, Sakuramoto H, Nakamura N, Kurihara T, Tsubota K, Miyake Y, Yoshiake K, Iwata T, Tsunoda K; Japan Eye Genetics Consortium Study Group.
  • Journal Title: Am J Med Genet C Semin Med Genet. Volume: 184 Issue: 3 Pages: 675-693
  • DOI: 10.1002/ajmg.c.31830
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic defects of CHM and visual acuity outcome in 24 choroideremia patients from 16 Japanese families (2020)
  • Author(s): Hayashi Takaaki、Kameya Shuhei、Mizobuchi Kei、Kubota Daiki、Kikuchi Sachiko、Yoshitake Kazutoshi、Mizota Atsushi、Murakami Akira、Iwata Takeshi、Nakano Tadashi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15883-15883
  • DOI: 10.1038/s41598-020-72623-1
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake disease); EAOMD Report No.1 (2019)
  • Author(s): Fujinami Kaoru、Yang Lizhu、Joo Kwangsic、Tsunoda Kazushige、Kameya Shuhei、Hanazono Gen、Fujinami-Yokokawa Yu、Arno Gavin、Kondo Mineo、Nakamura Natsuko、Kurihara Toshihide、Tsubota Kazuo、Zou Xuan、Li Hui、Park Kyu Hyung、Iwata Takeshi、Miyake Yozo、Woo Se Joon、Sui Ruifang
  • Journal Title: Ophthalmology Volume: - Issue: 10 Pages: 1432-1444
  • DOI: 10.1016/j.ophtha.2019.04.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phenotypical Characteristics of POC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance (2019)
  • Author(s): Kameya Shuhei、Fujinami Kaoru、Ueno Shinji、Hayashi Takaaki、Kuniyoshi Kazuki、Ideta Ryuichi、Kikuchi Sachiko、Kubota Daiki、Yoshitake Kazutoshi、Katagiri Satoshi、Sakuramoto Hiroyuki、Kominami Taro、Terasaki Hiroko、Yang Lizhu、Fujinami-Yokokawa Yu、Liu Xiao、Arno Gavin、Pontikos Nikolas、
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 60 Issue: 10 Pages: 3432-3432
  • DOI: 10.1167/iovs.19-26650
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autosomal dominant optic atrophy with OPA1 gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort. (2019)
  • Author(s): Maeda-Katahira A, Nakamura N, Hayashi T, Katagiri S, Shimizu S, Ohde H, Matsunaga T, Kaga K, Nakano T, Kameya S, Matsuura T, Fujinami K1, Iwata T, Tsunoda K.
  • Journal Title: Molecular Vision Volume: 25 Pages: 559-573
  • Peer Reviewed / Open Access
• [Journal Article] Novel homozygous in-frame deletion of GNAT1 gene causes golden appearance of fundus and reduced scotopic ERGs similar to that in Oguchi disease in Japanese family (2019)
  • Author(s): Kubota Daiki、Oishi Noriko、Gocho Kiyoko、Kikuchi Sachiko、Yamaki Kunihiko、Igarashi Tsutomu、Takahashi Hiroshi、Ishida Nobuo、Iwata Takeshi、Mizota Atsushi、Kameya Shuhei
  • Journal Title: Ophthalmic Genetics Volume: 40 Issue: 5 Pages: 480-487
  • DOI: 10.1080/13816810.2019.1686159
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings (2019)
  • Author(s): Nakamura Natsuko、Tsunoda Kazushige、Mizuno Yoshinobu、Usui Tomoaki、Hatase Tetsuhisa、Ueno Shinji、Kuniyoshi Kazuki、Hayashi Takaaki、Katagiri Satoshi、Kondo Mineo、Kameya Shuhei、Yoshitake Kazutoshi、Fujinami Kaoru、Iwata Takeshi、Miyake Yozo
  • Journal Title: Investigative Opthalmology & Visual Science Volume: 60 Issue: 14 Pages: 4691-4691
  • DOI: 10.1167/iovs.19-27486
  • Peer Reviewed / Open Access
• [Presentation] HK１遺伝子異常を認めた常染色体優性網膜色素変性症一家系のAO解析 (2020)
  • Author(s): 久保田 大紀、大石 典子、後町 清子、五十嵐 勉、山木 邦比古、亀谷 修平、高橋 浩
  • Organizer: 第68回 日本臨床視覚電気生理学会
• [Presentation] 黄斑ジストロフィを呈したm.3243A>G変異によるmaternally inherited diabetes and deafness (MIDD) の１症例 (2020)
  • Author(s): 大石典子、久保田大紀、武田幸人、林美香、後町清子、山木邦比古、小早川信一郎、五十嵐勉、高橋浩、亀谷修平
  • Organizer: 第68回 日本臨床視覚電気生理学会
• [Presentation] KCNV2網膜症における中心窩錐体の冗長性 (2020)
  • Author(s): 小柳 俊人、上野 真治、林 孝彰、 亀谷 修平、後町 清子、 園田 康平、 伊藤逸毅
  • Organizer: 第68回 日本臨床視覚電気生理学会
• [Presentation] 非典型的な黄斑病変を示した先天網膜分離症の1例 (2020)
  • Author(s): 永江由季，國吉一樹，林 孝彰，近藤千桜里，亀谷修平，岩田 岳，日下俊次
  • Organizer: 第68回 日本臨床視覚電気生理学会
• [Presentation] BDNF発現アデノ随伴ウイルスベクターtm-scAAV2-BDNFを用いた網膜内層障害の遺伝子治療 (2020)
  • Author(s): 塩澤朝香、五十嵐勉、小林舞香、中元兼二、亀谷修平、藤下繁人、高橋浩、岡田尚巳
  • Organizer: 日本眼科学会総会
• [Presentation] 「コロイデレミア」 シンポジウム2「網脈絡膜ジストロフィの最前線 （JEGCスタディ総括、Part 2）」 (2019)
  • Author(s): 亀谷修平
  • Organizer: 第67回日本臨床視覚電気生理学会
• [Presentation] A novel homozygous in-frame deletion of GNAT1 gene cause golden discolouration of the fundus and reduced dark-adapted ERG similar to characteristics of Oguchi disease in a Japanese family (2019)
  • Author(s): Shuhei Kameya, Daiki Kubota, Kiyoko Gocho, Sachiko Kikuchi, Kunihiko Yamaki, Tsutomu Igarashi, Hiroshi Takahashi, Nobuo Ishida, Kazutoshi Yoshitake, Takeshi Iwata, Atsushi Mizota
  • Organizer: ARVO 2019
  • Int'l Joint Research
• [Presentation] Functional Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake’s disease); EAOMD Report No.2 (2019)
  • Author(s): Lizhu Yang, Kwangsic Joo, Kazushige Tsunoda, Mineo Kondo, Yu Yokokawa Fujinami, Anthony G. Robson, Toshihide Kurihara, Kazuo Tsubota, Shuhei Kameya, Takeshi Iwata, Xuan Zou, Kyu Hyung Park, Yozo Miyake, Se Joon Woo, Ruifang Sui, Kaoru Fujinami
  • Organizer: ARVO 2019
  • Int'l Joint Research
• [Presentation] Japan Eye Genetics Consortium: National Cohort Survey and Whole Exome Sequencing Results (2019)
  • Author(s): Kaoru Fujinami, Kazutoshi Yoshitake, Takaaki Hayashi, Kazuki Kuniyoshi, Shinji Ueno, Mineo Kondo, Kei Shinoda, Shuhei Kameya, Nobuhisa Nao-i, Hiroyuki Kondo, Yozo Miyake, Takeshi Iwata, Kazushige Tsunoda
  • Organizer: ARVO 2019
  • Int'l Joint Research
• [Presentation] A novel homozygous in-frame deletion of GNAT1 gene cause golden discolouration of the fundus and reduced dark-adapted ERG similar to that of Oguchi disease in a Japanese family (2019)
  • Author(s): Shuhei Kameya, Daiki Kubota, Kiyoko Gocho, Sachiko Kikuchi, Kunihiko Yamaki, Tsutomu Igarashi, Hiroshi Takahashi, Nobuo Ishida, Kazutoshi Yoshitake, Takeshi Iwata, Atsushi Mizota
  • Organizer: ISGEDR 2019
  • Int'l Joint Research
• [Presentation] 眼底動脈壁所見と生活習慣病に関する検討 (2019)
  • Author(s): 山口祐司、岡島史宜、仲村優子、長峯朋子、周東佑樹、久保田大紀、後町清子、亀谷修平、高橋浩、杉原仁、江本直也
  • Organizer: 第62回 日本糖尿病学会
• [Presentation] 眼底動脈壁所見と生活習慣病に関する検討 (2019)
  • Author(s): 山口祐司、岡島史宜、仲村優子、長峯朋子、周東佑樹、久保田大紀、後町清子、亀谷修平、高橋浩、杉原仁、江本直也
  • Organizer: 第51回 日本動脈硬化学会
• [Presentation] Rhodopsin（RHO）遺伝子に新規1塩基欠損変異を認めた常染色体優性杆体錐体ジストロフィの1家系 (2019)
  • Author(s): 久保田大紀、後町清子、大石典子、丸山佳織、武田幸人、鈴木界、山木邦比古、高橋浩、亀谷修平
  • Organizer: 第67回 日本臨床視覚電気生理学会
• [Presentation] 全視野ERGで錐体反応良好な黄斑ジストロフィに新規GUCY2D 遺伝子変異を認めた１例 (2019)
  • Author(s): 武田幸人、久保田大紀、後町清子、大石典子、鈴木 界、丸山佳織、山木邦比古、高橋 浩、亀谷修平
  • Organizer: 第73回 日本臨床眼科学会総会
• [Book] 後眼部アトラス (2019)
  • Author(s): 亀谷修平（共著）
  • Total Pages: 430
  • Publisher: 総合医学社
  • ISBN: 9784883786862