研究者詳細 - 西口　康二

開放隅角緑内障1家系におけるOPTN遺伝子の新規N51T変異の同定

前川重人, 橋本和軌, 志賀由己浩, 津田聡, 面高宗子, 横山悠, 西口康二, 中澤徹, 日本緑内障学会遺伝子研究班

日本緑内障学会抄録集 30回巻頁： 184 - 184 2019年9月

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy 査読有り国際誌

Nikopoulos, K; Cisarova, K; Quinodoz, M; Koskiniemi-Kuendig, H; Miyake, N; Farinelli, P; Rehman, AU; Khan, MI; Prunotto, A; Akiyama, M; Kamatani, Y; Terao, C; Miya, F; Ikeda, Y; Ueno, S; Fuse, N; Murakami, A; Wada, Y; Terasaki, H; Sonoda, KH; Ishibashi, T; Kubo, M; Cremers, FPM; Kutalik, Z; Matsumoto, N; Nishiguchi, KM; Nakazawa, T; Rivolta, C

NATURE COMMUNICATIONS 10 巻 ( 1 ) 頁： 2884 - 2884 2019年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Communications

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

DOI： 10.1038/s41467-019-10746-4

Retained Plasticity and Substantial Recovery of Rod-Mediated Visual Acuity at the Visual Cortex in Blind Adult Mice with Retinal Dystrophy 査読有り

Quantitative analysis of the macula with optical coherence tomography angiography in normal Japanese subjects: The Taiwa Study. 査読有り国際誌

Sato R, Kunikata H, Asano T, Aizawa N, Kiyota N, Shiga Y, Nishiguchi KM, Kato K, Nakazawa T

Scientific reports 9 巻 ( 1 ) 頁： 8875 - 8875 2019年6月

Correlation between aqueous flare and residual visual field area in retinitis pigmentosa. 査読有り国際誌

Nishiguchi KM, Yokoyama Y, Kunikata H, Abe T, Nakazawa T

The British journal of ophthalmology 103 巻 ( 4 ) 頁： 475 - 480 2019年4月

Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum. 査読有り

Verbakel SK, van Huet RAC, den Hollander AI, Geerlings MJ, Kersten E, Klevering BJ, Klaver CCW, Plomp AS, Wesseling NL, Bergen AAB, Nikopoulos K, Rivolta C, Ikeda Y, Sonoda KH, Wada Y, Boon CJF, Nakazawa T, Hoyng CB, Nishiguchi KM

Investigative ophthalmology & visual science 60 巻 ( 4 ) 頁： 1192 - 1203 2019年3月

Macular degeneration as a common cause of visual loss in spinocerebellar ataxia type 1 (SCA1) patients. 査読有り

Nishiguchi KM, Aoki M, Nakazawa T, Abe T

Ophthalmic genetics 40 巻 ( 1 ) 頁： 49 - 53 2019年2月

Alternative methods to detect anti-TRPM1 antibodies. 査読有り国際誌

Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

Clinical & experimental ophthalmology 47 巻 ( 1 ) 頁： 148 - 149 2019年1月

Nishiguchi, KM; Fujita, K; Tokashiki, N; Komamura, H; Takemoto-Kimura, S; Okuno, H; Bito, H; Nakazawa, T

MOLECULAR THERAPY 26 巻 ( 10 ) 頁： 2397 - 2406 2018年10月

記述言語：英語出版者・発行元：Molecular Therapy

In patients born blind with retinal dystrophies, understanding the critical periods of cortical plasticity is important for successful visual restoration. In this study, we sought to model childhood blindness and investigate the plasticity of visual pathways. To this end, we generated double-mutant (Pde6ccpfl1/cpfl1Gnat1IRD2/IRD2) mice with absent rod and cone photoreceptor function, and we evaluated their response for restoring rod (GNAT1) function through gene therapy. Despite the limited effectiveness of gene therapy in restoring visual acuity in patients with retinal dystrophy, visual acuity was, unexpectedly, successfully restored in the mice at the level of the primary visual cortex in this study. This success in visual restoration, defined by changes in the quantified optokinetic response and pattern visually evoked potential, was achieved regardless of the age at treatment (up to 16 months). In the contralateral visual cortex, cortical plasticity, tagged with light-triggered transcription of Arc, was also restored after the treatment in blind mice carrying an Arc promoter-driven reporter gene, dVenus. Our results demonstrate the remarkable plasticity of visual circuits for one of the two photoreceptor mechanisms in older as well as younger mice with congenital blindness due to retinal dystrophies. Nishiguchi et al. show that recovery of rod-mediated visual acuity is possible at the level of the visual cortex after functional restoration of the rods, even in adults. The remarkable plasticity of visual circuits shown provides an important insight into the restoration of vision.

DOI： 10.1016/j.ymthe.2018.07.012

Reliable detection of low visual acuity in mice with pattern visually evoked potentials. 査読有り

Tokashiki N, Nishiguchi KM, Fujita K, Sato K, Nakagawa Y, Nakazawa T

Scientific reports 8 巻 ( 1 ) 頁： 15948 2018年10月

Metabolomic changes in the mouse retina after optic nerve injury. 査読有り国際誌

Sato K, Saigusa D, Saito R, Fujioka A, Nakagawa Y, Nishiguchi KM, Kokubun T, Motoike IN, Maruyama K, Omodaka K, Shiga Y, Uruno A, Koshiba S, Yamamoto M, Nakazawa T

Scientific reports 8 巻 ( 1 ) 頁： 11930 - 11930 2018年8月

Ecel1 Knockdown With an AAV2-Mediated CRISPR/Cas9 System Promotes Optic Nerve Damage-Induced RGC Death in the Mouse Retina. 査読有り国際誌

Sato K, Shiga Y, Nakagawa Y, Fujita K, Nishiguchi KM, Tawarayama H, Murayama N, Maekawa S, Yabana T, Omodaka K, Katayama S, Feng Q, Tsuda S, Nakazawa T

Investigative ophthalmology & visual science 59 巻 ( 10 ) 頁： 3943 - 3951 2018年8月

Prevalence of anti-retinal antibodies in epiretinal membranes and macular holes. 査読有り国際誌

Kunikata H, Fujita K, Nishiguchi KM, Nakazawa T

Clinical & experimental ophthalmology 46 巻 ( 5 ) 頁： 556 - 558 2018年7月

Levels of Anti-Retinal Antibodies in Retinal Detachment and Proliferative Vitreoretinopathy. 査読有り国際誌

Ichinohasama R, Nishiguchi KM, Fujita K, Aizawa N, Inoue T, Sasaki E, Kunikata H, Nakazawa T

Current eye research 43 巻 ( 6 ) 頁： 804 - 809 2018年6月

Anti-TRPM1 antibodies in patients with retinal degeneration. 査読有り国際誌

Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

Clinical & experimental ophthalmology 46 巻 ( 9 ) 頁： 1087 - 1089 2018年6月

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma 査読有り

Shiga, Y; Akiyama, M; Nishiguchi, KM; Sato, K; Shimozawa, N; Takahashi, A; Momozawa, Y; Hirata, M; Matsuda, K; Yamaji, T; Iwasaki, M; Tsugane, S; Oze, I; Mikami, H; Naito, M; Wakai, K; Yoshikawa, M; Miyake, M; Yamashiro, K; Kashiwagi, K; Iwata, T; Mabuchi, F; Takamoto, M; Ozaki, M; Kawase, K; Aihara, M; Araie, M; Yamamoto, T; Kiuchi, Y; Nakamura, M; Ikeda, Y; Sonoda, KH; Ishibashi, T; Nitta, K; Iwase, A; Shirato, S; Oka, Y; Satoh, M; Sasaki, M; Fuse, N; Suzuki, Y; Cheng, CY; Khor, CC; Baskaran, M; Perera, S; Aung, T; Vithana, EN; Bailey, JNC; Kang, JH; Pasquale, LR; Haines, JL; Wiggs, JL; Burdon, KP; Gharahkhani, P; Hewitt, AW; Mackey, DA; MacGregor, S; Craig, JE; Allingham, RR; Hauser, M; Ashaye, A; Budenz, DL; Akafo, S; Williams, SEI; Kamatani, Y; Nakazawa, T; Kubo, M

HUMAN MOLECULAR GENETICS 27 巻 ( 8 ) 頁： 1486 - 1496 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Human Molecular Genetics

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P<5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

DOI： 10.1093/hmg/ddy053