Trial to identify the causative gene of periodic strabismus

• Project/Area Number: 16K11309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Nishina Sachiko 国立研究開発法人国立成育医療研究センター, 感覚器・形態外科部, 医長 (40237954)
• Research Collaborator: AZUMA Noriyuki 国立成育医療研究センター ; FUKAMI Maki 国立成育医療研究センター ; NISHINA Hiroshi 東京医科歯科大学
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 斜視 / 周期性斜視 / エクソン解析 / 概日リズム / ゼブラフィッシュ / 時計遺伝子 / モデル生物 / 弱視斜視 / 小児眼科

Outline of Final Research Achievements

In strabismus, the eyes are not properly aligned with the target. Strabismus is an intractable disease that causes lifelong QOL decline due to abnormalities in binocular function. However, the cause remains unknown.
We have been trying to identify genetic factors in the special strabismus, periodic strabismus. So far, genome analysis of 2 cases of periodic exotropia has been performed. Interestingly, point mutations have been found in the exon regions. We also examined the molecular mechanism of "circadian rhythm", which is suggested to be related to periodic strabismus, using a model organism zebrafish. As a result, it was revealed that the light-induced clock gene regulates the behavioral rhythm through the synchronization of the cellular clocks.

Academic Significance and Societal Importance of the Research Achievements

斜視は、両眼の視線が正しく目標に合致していない状態である。視覚刺激に対する感受性の高い乳幼児期に斜視が起こると、斜視眼の抑制、弱視、対応異常をきたし、正常な両眼視機能が発達しない。一方、学童期以降に斜視が起こると複視をきたす。斜視は両眼視機能の異常によって生涯にわたるQOL低下をきたす難治性疾患である。斜視の頻度は、人種差はあるものの国内外で２～４％と高い。しかしながら、斜視の原因に関しては、遺伝的要因と環境要因の双方が提唱されているが、不明のままである。それ故、斜視の原因解明は、科学的にも社会的にも重要である。本研究生は、その糸口になり研究成果と考えられる。

Research Products

• [Journal Article] The clock components Period2, Cryptochrome1a, and Cryptochrome2a function in establishing light-dependent behavioral rhythms and/or total activity levels in zebrafish (2019)
  • Author(s): Hirayama J, Alifu Y, Hamabe R, Yamaguchi S, Tomita J, Maruyama Y, Asaoka Y , Nakahama K, Tamaru T, Takamatsu K, Takamatsu N, Hattori A, Nishina S, Azuma N, Kawahara A, Kume K, Nishina H.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 196-196
  • DOI: 10.1038/s41598-018-37879-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing (2018)
  • Author(s): Hosono Katsuhiro、Nishina Sachiko、Yokoi Tadashi、Katagiri Satoshi、Saitsu Hirotomo、Kurata Kentaro、Miyamichi Daisuke、Hikoya Akiko、Mizobuchi Kei、Nakano Tadashi、Minoshima Shinsei、Fukami Maki、Kondo Hiroyuki、Sato Miho、Hayashi Takaaki、Azuma Noriyuki、Hotta Yoshihiro
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8279-8279
  • DOI: 10.1038/s41598-018-26524-z
  • Peer Reviewed / Open Access
• [Journal Article] Incidence of side effects of topical atropine sulfate and cyclopentolate hydrochloride for cycloplegia in Japanese children: a multicenter study. (2018)
  • Author(s): Wakayama Akemi, Nishina Sachiko, Miki Atsushi, Utsumi Takashi, Sugasawa Jun, Hayashi Takao, Sato Miho, Kimura Akiko, Fujikado Takashi.
  • Journal Title: Japanese Journal of Ophthalmology Volume: 62 Issue: 5 Pages: 531-536
  • DOI: 10.1007/s10384-018-0612-7
  • Peer Reviewed
• [Journal Article] Surgical treatments for fibrous tissue extending to the posterior retina in eyes with familial exudative vitreoretinopathy. (2018)
  • Author(s): Takahashi M, Yokoi T, Katagigi S, Yoshida-Uemura T, Nishina, S, Azuma N
  • Journal Title: Jpn J Ophthalmol Volume: 62 Issue: 1 Pages: 63-67
  • DOI: 10.1007/s10384-017-0547-4
  • NAID: 210000165825
  • Peer Reviewed
• [Journal Article] Retinal structure and function in eyes with optic nerve hypoplasia. (2017)
  • Author(s): Katagiri S, Nishina S, Yokoi T, Mikami M, Nakayama Y, Tanaka M, Azuma N.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 42480-42480
  • DOI: 10.1038/srep42480
  • Peer Reviewed / Open Access
• [Journal Article] A. Anteroposterior Patterning of Gene Expression in the Human Infant Sclera: Chondrogenic Potential and Wnt Signaling. (2017)
  • Author(s): Seko Y, Azuma N, Yokoi T, Kami D, Ishii R, Nishina S, Toyoda M, Shimokawa H, Umezawa
  • Journal Title: Curr Eye Res Volume: 42（1） Issue: 1 Pages: 145-154
  • DOI: 10.3109/02713683.2016.1143015
  • Peer Reviewed / Open Access
• [Journal Article] Long-term surgical outcome of conventional trabeculotomy for childhood glaucoma. (2017)
  • Author(s): Ozawa H, Yamane M, Inoue E, Yoshida-Uemura T, Katagiri S, Yokoi T, Nishina S, Azuma N.
  • Journal Title: Jpn J Ophthalmol Volume: 印刷中 Issue: 3 Pages: 237-244
  • DOI: 10.1007/s10384-017-0506-0
  • Peer Reviewed / Open Access
• [Journal Article] Different foveal schisis patterns in each retinal layer in eyes with hereditary juvenile retinoschisis evaluated by en-face optical coherence tomography. (2017)
  • Author(s): Yoshida-Uemura T, Katagiri S, Yokoi T, Nishina S, Azuma N.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 255（4） Issue: 4 Pages: 719-723
  • DOI: 10.1007/s00417-016-3552-2
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of a toddler with bilateral bullous retinoschisis with a novel RS1 mutation. (2017)
  • Author(s): Katagiri S, Tanaka S, Yokoi T, Hayashi T, Matsuzaka E, Ueda K, Yoshida-Uemura T, Arakawa A, Nishina S, Kadonosono K, Azuma N.
  • Journal Title: American Journal of Ophthalmology Case Reports Volume: 5 Pages: 76-80
  • DOI: 10.1016/j.ajoc.2016.12.009
  • Peer Reviewed / Open Access
• [Journal Article] Atypical intravitreal growth of retinoblastoma with a multi-branching configuration (2017)
  • Author(s): Nishina Sachiko、Katagiri Satoshi、Nakazawa Atsuko、Kiyotani Chikako、Yokoi Tadashi、Azuma Noriyuki
  • Journal Title: Am J Ophthalmol Case Rep Volume: 7 Pages: 4-8
  • DOI: 10.1016/j.ajoc.2017.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of Retinal Breaks and Surgical Outcomes in Rhegmatogenous Retinal Detachment in Familial Exudative Vitreoretinopathy (2017)
  • Author(s): Katagiri Satoshi、Yokoi Tadashi、Yoshida-Uemura Tomoyo、Nishina Sachiko、Azuma Noriyuki
  • Journal Title: Ophthalmology Retina Volume: 5 Issue: 7 Pages: 76-80
  • DOI: 10.1016/j.oret.2017.11.003
  • Peer Reviewed / Open Access
• [Journal Article] ATYPICAL FORM OF RETINOPATHY OF PREMATURITY WITH SEVERE FIBROVASCULAR PROLIFERATION IN THE OPTIC DISC REGION (2017)
  • Author(s): Yokoi T, Katagiri S, Hiraoka M, Nakayama Y, Hosono K, Hotta Y, Nishina S, Azuma N
  • Journal Title: RETINA Volume: 印刷中 Issue: 8 Pages: 1-1
  • DOI: 10.1097/iae.0000000000001779
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of neuroactive agents on axonal growth and pathfinding of retinal ganglion cells generated from human stem cells (2017)
  • Author(s): Yokoi Tadashi、Tanaka Taku、Matsuzaka Emiko、Tamalu Fuminobu、Watanabe Shu-Ichi、Nishina Sachiko、Azuma Noriyuki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 16757-16757
  • DOI: 10.1038/s41598-017-16727-1
  • Peer Reviewed / Open Access
• [Journal Article] Atypical intravitreal growth of retinoblastoma with a multi-branching configuration. (2017)
  • Author(s): Nishina S, Katagiri S, Nakazawa A, Kiyotani C, Yokoi T, Azuma N.
  • Journal Title: Am J Ophthalmol Case Rep Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical features of a toddler with bilateral bullous retinoschisis with a novel RS1 mutation. (2017)
  • Author(s): Katagiri S, Tanaka S, Yokoi T, Hayashi T, Matsuzaka E, Ueda K, Yoshida-Uemura T, Arakawa A, Nishina S, Kadonosono K, Azuma N.
  • Journal Title: Am J Ophthalmol Case Rep. Volume: 5 Pages: 76-80
  • Peer Reviewed
• [Journal Article] The mevalonate pathway regulates primitive streak formation via protein farnesylation (2016)
  • Author(s): Okamoto-Uchida Y, Yu R, Miyamura N, Arima N, Ishigami-Yuasa M, Kagechika H, Yoshida S, Hosoya T, Nawa M, Kasama T, Asaoka Y, Alois RW, Elling U, Penninger JM, Nishina S, Azuma N, Nishina H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37697-37697
  • DOI: 10.1038/srep37697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outer retinal deformity detected by optical coherence tomography in eyes with foveal hypoplasia. (2016)
  • Author(s): Katagiri S, Yokoi T, Mikami M, Nishina S, Azuma N.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 254 Pages: 2197-2201
  • Peer Reviewed
• [Journal Article] Successful scleral buckling of late-onset visual decrease in eye with retinal folds. (2016)
  • Author(s): Nakayama Y, Katagiri S, Yokoi T, Ui M, Nishina S, Azuma N.
  • Journal Title: Doc Ophthalmol. Volume: 133 Pages: 145-149
  • Peer Reviewed
• [Journal Article] Electroretinographic effects of retinal dragging and retinal folds in eyes with familial exudative vitreoretinopathy. (2016)
  • Author(s): Yaguchi Y, Katagiri S, Fukushima Y, Yokoi T, Nishina S, Kondo M, Azuma N.
  • Journal Title: Sci Rep. Volume: 6 Pages: 30523-30523
  • Peer Reviewed / Open Access
• [Journal Article] Generation of retinal ganglion cells with functional axons from mouse embryonic stem cells and induced pluripotent stem cells. (2016)
  • Author(s): Tanaka T, Yokoi T, Tamalu F, Watanabe S, Nishina S, Azuma N.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 57 Issue: 7 Pages: 3348-3359
  • DOI: 10.1167/iovs.16-19166
  • Peer Reviewed / Open Access
• [Journal Article] Genotype-phenotype correlation of the PAX6 gene mutations in aniridia (2016)
  • Author(s): Yokoi T, Nishina S, Fukami M, Ogata T, Hosono K, Hotta Y, Azuma N.
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 15052-15052
  • DOI: 10.1038/hgv.2015.52
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure and morphology of radial retinal folds with familial exudative vitreoretinopathy. (2016)
  • Author(s): Katagiri S, Yokoi T, Nishina S, Azuma N.
  • Journal Title: Ophthalmology Volume: 123(3) Issue: 3 Pages: 666-8
  • DOI: 10.1016/j.ophtha.2015.09.010
  • Peer Reviewed / Open Access
• [Journal Article] Use of the Delphi process in paediatric cataract management. (2016)
  • Author(s): Sarafino M, Trivedi RH, Levin AV, Wilson ME, Nucci P, Lambert SR, Nischal KK, Plager DA, Bremond-Gignac D, Kekunnaya R, Nishina S, Tehrani NN, Ventura MC.
  • Journal Title: Br J Ophthalmol Volume: 100 Pages: 611-615
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Abnormal traction of the vitreous detected by swept-source optical coherence tomography is related to the maculopathy associated with optic disc pits. (2016)
  • Author(s): Yokoi T, Nakayama Y, Nishina S, Azuma N.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: in press Issue: 4 Pages: 675-682
  • DOI: 10.1007/s00417-015-3114-z
  • Peer Reviewed / Open Access
• [Presentation] 小児白内障の検査．教育セミナー1小児白内障・緑内障の検査と治療 (2018)
  • Author(s): 仁科幸子
  • Organizer: 第122回日本眼科学会総会
• [Presentation] 小児の神経眼科. インストラクションコース17 やさしい神経眼科 (2018)
  • Author(s): 仁科幸子
  • Organizer: 第72回日本臨床眼科学会
• [Presentation] Leber先天盲. シンポジウム6 小児網膜変性疾患の病態と診断 (2018)
  • Author(s): 仁科幸子
  • Organizer: 第72回日本臨床眼科学会
• [Presentation] 周期性斜視７例の臨床像と治療経過. (2018)
  • Author(s): 堤典子、仁科幸子、吉田朋世、横井匡、東範行
  • Organizer: 第72回日本臨床眼科学会
• [Presentation] 乳幼児健診において小児科医が知っておくべき眼疾患とその対応 (2018)
  • Author(s): 仁科幸子
  • Organizer: 大阪小児科医会 第7回成育医療研修会
  • Invited
• [Presentation] 見逃しに注意；小児眼科医からのアドバイス (2018)
  • Author(s): 仁科幸子
  • Organizer: 乳幼児健診を中心とする小児科医のための研修会PartⅢ～一歩進んだ乳幼児健診を目指して～
  • Invited
• [Presentation] 乳幼児の気をつけたい目の病気 (2018)
  • Author(s): 仁科幸子
  • Organizer: 母子保健相談員研修会
  • Invited
• [Presentation] 視機能の発達・小児によくみられる眼疾患 (2018)
  • Author(s): 仁科幸子
  • Organizer: 母子愛育会 地域母子保健3 乳幼児期に見られる諸問題
  • Invited
• [Presentation] OCT and ERG initial findings in Leber congenital amaurosis and genetic analysis (2018)
  • Author(s): 1.Sachiko Nishina, Tadashi Yokoi, Tomoyo Yoshida, Maki Fukami, Katsuhiro Hosono, Kentaro Kurata, Yoshihiro Hotta, Noriyuki Azuma
  • Organizer: 44rd Annual Meeting, American Association for Pediatric Ophthalmology and Strabismus
  • Int'l Joint Research / Invited
• [Presentation] Early detection and management of deprivation amblyopia. (2017)
  • Author(s): Nishina S.
  • Organizer: 32th APAO Congress
  • Place of Presentation: Taipei
  • Year and Date: 2017-03-01
  • Int'l Joint Research / Invited
• [Presentation] 未熟児網膜症の診断と治療の現状 (2017)
  • Author(s): 仁科幸子
  • Organizer: The 2nd SCOOP Meeting
  • Place of Presentation: 浜松
  • Invited
• [Presentation] 気をつけたい小児眼疾患・病診連携のポイント (2017)
  • Author(s): 仁科幸子
  • Organizer: 第12回西東京市眼科医会学術講演会
  • Place of Presentation: 西東京市
  • Invited
• [Presentation] 病診連携 よくある眼底疾患 (2017)
  • Author(s): 仁科幸子
  • Organizer: 日本眼科医会第72回生涯教育講座
  • Place of Presentation: 東京
  • Invited
• [Presentation] 病診連携 よくある眼底疾患―診断と治療のコンセンサス (2017)
  • Author(s): 仁科幸子
  • Organizer: 日本眼科医会第72回生涯教育講座
  • Place of Presentation: 神戸
  • Invited
• [Presentation] 0歳から見つけたい！小児の眼疾患と弱視 (2017)
  • Author(s): 仁科幸子
  • Organizer: 第550回葛飾区小児科医会講演会
  • Place of Presentation: 葛飾
  • Invited
• [Presentation] 病診連携 よくある眼底疾患―診断と治療のコンセンサス (2017)
  • Author(s): 仁科幸子
  • Organizer: 日本眼科医会第72回生涯教育講座
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 乳幼児の前眼部疾患の診かた (2016)
  • Author(s): 仁科幸子
  • Organizer: 第25回千葉臨床眼科フォーラム
  • Place of Presentation: 幕張
  • Invited
• [Presentation] 小児の弱視早期発見の重要性 (2016)
  • Author(s): 仁科幸子
  • Organizer: 第5回日本小児診療多職種研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 乳幼児健診で気になる眼の病気 (2016)
  • Author(s): 仁科幸子
  • Organizer: 第10回所沢市乳幼児健康診査医師講習会
  • Place of Presentation: 所沢
  • Invited
• [Presentation] 乳幼児の前眼部疾患の診かた (2016)
  • Author(s): 仁科幸子
  • Organizer: 第6回山形眼科フォーラム
  • Place of Presentation: 山形
  • Invited
• [Book] 眼科診療クオリファイ 30眼の発生と解剖・機能 (2016)
  • Author(s): 仁科幸子
  • Total Pages: 444
  • Publisher: 中山書店