Faculty Profiles - Koji Nishiguchi

Papers - Koji Nishiguchi

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Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients. Reviewed

Koyanagi Y, Akiyama M, Nishiguchi KM, Momozawa Y, Kamatani Y, Takata S, Inai C, Iwasaki Y, Kumano M, Murakami Y, Omodaka K, Abe T, Komori S, Gao D, Hirakata T, Kurata K, Hosono K, Ueno S, Hotta Y, Murakami A, Terasaki H, Wada Y, Nakazawa T, Ishibashi T, Ikeda Y, Kubo M, Sonoda KH

Journal of medical genetics Vol. 56 ( 10 ) page： 662 - 670 2019.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ

<sec><title>Background</title>The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.

</sec><sec><title>Methods</title>A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.

</sec><sec><title>Results</title>We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (<italic>EYS</italic>, <italic>USH2A</italic>, <italic>RP1L1</italic>, <italic>RHO</italic>, <italic>RP1</italic> and <italic>RPGR</italic>) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in <italic>EYS</italic> [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in <italic>USH2A</italic>, p.(Arg658*) in <italic>RP1L1</italic>, p.(Gly2186Glu) in <italic>EYS</italic> and p.(Ile535Asn) in <italic>PDE6B</italic>] and p.(Cys934Trp) in <italic>USH2A</italic> were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in <italic>RHO</italic>, p.(Arg872fs) in <italic>RP1</italic>, p.(Arg41Trp) in <italic>CRX</italic> and p.(Gly381fs) in <italic>PRPF31</italic>] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.

</sec><sec><title>Conclusions</title>East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

</sec>

DOI： 10.1136/jmedgenet-2018-105691

Web of Science

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PubMed

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 Vol. 30回 page： 184 - 184 2019.9

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Reviewed International journal

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 Vol. 10 ( 1 ) page： 2884 - 2884 2019.6

Language：English Publishing type：Research paper (scientific journal)

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

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Quantitative analysis of the macula with optical coherence tomography angiography in normal Japanese subjects: The Taiwa Study. Reviewed International journal

Risa Sato, Hiroshi Kunikata, Toshifumi Asano, Naoko Aizawa, Naoki Kiyota, Yukihiro Shiga, Koji M Nishiguchi, Keiichi Kato, Toru Nakazawa

Scientific reports Vol. 9 ( 1 ) page： 8875 - 8875 2019.6

Language：English Publishing type：Research paper (scientific journal)

This study evaluated age-related changes in the superficial and deep retinal capillary plexus (SCP and DCP, respectively) and in the foveal avascular zone (FAZ). SCP and DCP perfusion density (PD) were measured in optical coherence tomography angiography (OCTA) macular scans of 145 eyes of 145 healthy Japanese subjects, and findings were compared with SCP FAZ and clinical data. We found that age was negatively correlated with SCP and DCP PD (r = -0.17, P = 0.04 and r = -0.20, P = 0.02, respectively) and positively correlated with FAZ area (r = 0.18, P = 0.03). SCP and DCP PD were correlated with each other (r = 0.67, P < 0.001). FAZ area was negatively correlated with SCP PD, DCP PD and central macular thickness (CMT) (r = -0.18, P = 0.03; r = -0.25, P < 0.01; and r = -0.39, P < 0.001, respectively). FAZ was larger and CMT was lower (P = 0.01 and P < 0.001, respectively) in women than men. SCP and DCP PD were positively correlated with estimated glomerular filtration rate (r = 0.17, P = 0.03 and r = 0.24, P < 0.01, respectively). Multiple regression analysis confirmed that age independently affected DCP PD and FAZ (P = 0.02 and P < 0.01, respectively) and that CMT independently affected FAZ area (P < 0.001). Thus, normal subjects showed age-related decreases in macular PD and renal function. FAZ and CMT were related, suggesting that age-related changes in macular thickness also affect capillary vasculature.

DOI： 10.1038/s41598-019-45336-3

PubMed

Correlation between aqueous flare and residual visual field area in retinitis pigmentosa. Reviewed International journal

Koji M Nishiguchi, Yu Yokoyama, Hiroshi Kunikata, Toshiaki Abe, Toru Nakazawa

The British journal of ophthalmology Vol. 103 ( 4 ) page： 475 - 480 2019.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIMS: To investigate the relationship between aqueous flare, visual function and macular structures in retinitis pigmentosa (RP). METHODS: Clinical data from 123 patients with RP (227 eyes), 35 patients with macular dystrophy (68 eyes) and 148 controls (148 eyes) were analysed. The differences in aqueous flare between clinical entities and the correlation between aqueous flare (measured with a laser flare cell meter) versus visual acuity, visual field area (Goldmann perimetry) and macular thickness (optical coherence tomography) in patients with RP were determined. Influence of selected clinical data on flare was assessed using linear mixed-effects model. RESULTS: Aqueous flare was higher in patients with RP than patients with macular dystrophy or controls (p=7.49×E-13). Aqueous flare was correlated with visual field area (R=-0.379, p=3.72×E-9), but not with visual acuity (R=0.083, p=0.215). Macular thickness (R=0.234, p=3.74×E-4), but not foveal thickness (R=0.122, p=0.067), was positively correlated with flare. Flare was not affected by the presence of macular complications. All these associations were maintained when the right and the left eyes were assessed separately. Analysis by linear mixed-effects model revealed that age (p=8.58×E-5), visual field area (p=8.01×E-7) and average macular thickness (p=0.037) were correlated with flare. CONCLUSION: Aqueous flare and visual field area were correlated in patients with RP. Aqueous flare may reflect the degree of overall retinal degeneration more closely than the local foveal impairment.

DOI： 10.1136/bjophthalmol-2018-312225

PubMed

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

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 Vol. 60 ( 4 ) page： 1192 - 1203 2019.3

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

Nishiguchi KM, Aoki M, Nakazawa T, Abe T

Ophthalmic genetics Vol. 40 ( 1 ) page： 49 - 53 2019.2

Alternative methods to detect anti-TRPM1 antibodies. Reviewed International journal

Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

Clinical & experimental ophthalmology Vol. 47 ( 1 ) page： 148 - 149 2019.1

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

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

Molecular therapy : the journal of the American Society of Gene Therapy Vol. 26 ( 10 ) page： 2397 - 2406 2018.10

Reliable detection of low visual acuity in mice with pattern visually evoked potentials. Reviewed

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

Scientific reports Vol. 8 ( 1 ) page： 15948 2018.10

Metabolomic changes in the mouse retina after optic nerve injury. Reviewed International journal

Kota Sato, Daisuke Saigusa, Ritsumi Saito, Amane Fujioka, Yurika Nakagawa, Koji M Nishiguchi, Taiki Kokubun, Ikuko N Motoike, Kazuichi Maruyama, Kazuko Omodaka, Yukihiro Shiga, Akira Uruno, Seizo Koshiba, Masayuki Yamamoto, Toru Nakazawa

Scientific reports Vol. 8 ( 1 ) page： 11930 - 11930 2018.8

Language：English Publishing type：Research paper (scientific journal)

In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

DOI： 10.1038/s41598-018-30464-z

PubMed

Ecel1 Knockdown With an AAV2-Mediated CRISPR/Cas9 System Promotes Optic Nerve Damage-Induced RGC Death in the Mouse Retina. Reviewed International journal

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 Vol. 59 ( 10 ) page： 3943 - 3951 2018.8

Language：English Publishing type：Research paper (scientific journal)

Purpose: To assess the therapeutic potential of endothelin-converting enzyme-like 1 (Ecel1) in a mouse model of optic nerve crush. Methods: Ecel1 expression was evaluated with real time quantitative (qRT)-PCR, Western blotting, and immunohistochemistry in mouse retinas after optic nerve crush. Vinblastine administration to the optic nerve and the intravitreal injection of N-methyl-d-aspartate (NMDA) were used to assess Ecel1 gene expression. Ecel1 was deleted with an adeno-associated viral (AAV) clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9 system, and retinal ganglion cell (RGC) survival was investigated with retrograde labeling, qRT-PCR, and visual evoked potential. Results: Optic nerve crush induced Ecel1 expression specifically in the RGCs, peaking on day 4 after optic nerve crush. Ecel1 gene expression was induced by the vinblastine-induced inhibition of axonal flow, but not by NMDA-induced excitotoxicity, even though both are triggers of RGC death. Knockdown of Ecel1 promoted the loss of RGCs after optic nerve crush. Conclusions: Our data suggest that Ecel1 induction is part of the retinal neuroprotective response to axonal injury in mice. These findings might provide insight into novel therapeutic targets for the attenuation of RGC damage, such as occurs in traumatic optic neuropathy.

DOI： 10.1167/iovs.18-23784

PubMed

Prevalence of anti-retinal antibodies in epiretinal membranes and macular holes. Reviewed International journal

Hiroshi Kunikata, Kosuke Fujita, Koji M Nishiguchi, Toru Nakazawa

Clinical & experimental ophthalmology Vol. 46 ( 5 ) page： 556 - 558 2018.7

Levels of Anti-Retinal Antibodies in Retinal Detachment and Proliferative Vitreoretinopathy. Reviewed International journal

Reo Ichinohasama, Koji M Nishiguchi, Kosuke Fujita, Naoko Aizawa, Takashi Inoue, Erika Sasaki, Hiroshi Kunikata, Toru Nakazawa

Current eye research Vol. 43 ( 6 ) page： 804 - 809 2018.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The purpose of the study is to investigate the correlation between intraocular anti-retinal antibodies and clinical measurements in patients with rhegmatogenous retinal detachment (RRD) and proliferative vitreoretinopathy (PVR). MATERIAL AND METHODS: Aqueous humor and vitreous samples were collected from patients with RRD, PVR, and from control subjects with macular hole. The levels of total protein (TP), IgG, and anti-retinal antibodies were determined with a bicinchoninic acid assay, enzyme-linked immunosorbent assay, and dot blot, respectively. Correlations between these measurements were assessed using Pearson's correlation test. Analysis of variance followed by a post-hoc test or the Student t-test was used to compare differences between groups. RESULTS: The levels of anti-retinal antibodies and IgG were correlated with each other (P < 0.010). The IgG concentration was higher in patients with PVR than in controls in both the aqueous humor (P < 0.001) and the vitreous (P < 0.001), but not in patients with RRD. Conversely, TP levels and anti-retinal antibodies in both ocular fluids from RRD and PVR patients did not significantly differ from the controls. In a subgroup analysis, vitreal anti-retinal antibody levels were correlated with average macular thickness in the re-attached macula following surgery for macula-off RRD/PVR (P = 0.012). Furthermore, patients with post-operative cystoid macular edema had a higher level of vitreal anti-retinal antibodies than those without (P = 0.009). CONCLUSIONS: Intravitreal anti-retinal antibodies were increased in the eyes with maculopathy after surgical intervention for RRD/PVR.

DOI： 10.1080/02713683.2018.1451544

PubMed

Anti-TRPM1 antibodies in patients with retinal degeneration. Reviewed International journal

Nishiguchi KM, Fujita K, Inoue T, Nakazawa T

Clinical & experimental ophthalmology Vol. 46 ( 9 ) page： 1087 - 1089 2018.6

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma Reviewed

Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Masato Akiyama, Koji M. Nishiguchi, Kota Sato, Nobuhiro Shimozawa, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Isao Oze, Haruo Mikami, Mariko Naito, Kenji Wakai, Munemitsu Yoshikawa, Masahiro Miyake, Kenji Yamashiro, Kenji Kashiwagi, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Makoto Aihara, Makoto Araie, Tetsuya Yamamoto, Yoshiaki Kiuchi, Makoto Nakamura, Yasuhiro Ikeda, Koh-Hei Sonoda, Tatsuro Ishibashi, Koji Nitta, Aiko Iwase, Shiroaki Shirato, Yoshitaka Oka, Mamoru Satoh, Makoto Sasaki, Nobuo Fuse, Yoichi Suzuki, Ching-Yu Cheng, Chiea Chuen Khor, Mani Baskaran, Shamira Perera, Tin Aung, Eranga N. Vithana, Jessica N. Cooke Bailey, Jae H. Kang, Louis R. Pasquale, Jonathan L. Haines, Janey L. Wiggs, Kathryn P. Burdon, Puya Gharahkhani, Alex W. Hewitt, David A. Mackey, Stuart MacGregor, Jamie E. Craig, R. Rand Allingham, Micheal Hauser, Adeyinka Ashaye, Donald L. Budenz, Stephan Akafo, Susan E.I. Williams, Yoichiro Kamatani, Toru Nakazawa, Michiaki Kubo

Human Molecular Genetics Vol. 27 ( 8 ) page： 1486 - 1496 2018.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

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&lt
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

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Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa. Reviewed International journal

Yasuhiro Ikeda, Koji M Nishiguchi, Fuyuki Miya, Nobuhiro Shimozawa, Jun Funatsu, Shunji Nakatake, Kohta Fujiwara, Takashi Tachibana, Yusuke Murakami, Toshio Hisatomi, Shigeo Yoshida, Yasuhiro Yasutomi, Tatsuhiko Tsunoda, Toru Nakazawa, Tatsuro Ishibashi, Koh-Hei Sonoda

Investigative ophthalmology & visual science Vol. 59 ( 2 ) page： 826 - 830 2018.2

Language：English Publishing type：Research paper (scientific journal)

Purpose: To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods: First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results: Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. Conclusions: The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

DOI： 10.1167/iovs.17-22958

PubMed

Quantitative MRI evaluation of glaucomatous changes in the visual pathway. Reviewed International journal

Fukuda M, Omodaka K, Tatewaki Y, Himori N, Matsudaira I, Nishiguchi KM, Murata T, Taki Y, Nakazawa T

PloS one Vol. 13 ( 7 ) page： e0197027 2018

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The aims of this study were to investigate glaucomatous morphological changes quantitatively in the visual cortex of the brain with voxel-based morphometry (VBM), a normalizing MRI technique, and to clarify the relationship between glaucomatous damage and regional changes in the visual cortex of patients with open-angle glaucoma (OAG). METHODS: Thirty-one patients with OAG (age: 55.9 ± 10.7, male: female = 9: 22) and 20 age-matched controls (age: 54.9 ± 9.8, male: female = 10: 10) were included in this study. The cross-sectional area (CSA) of the optic nerve was manually measured with T2-weighed MRI. Images of the visual cortex were acquired with T1-weighed 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequencing, and the normalized regional visual cortex volume, i.e., gray matter density (GMD), in Brodmann areas (BA) 17, 18, and 19, was calculated with a normalizing technique based on statistic parametric mapping 8 (SPM8) analysis. We compared the regional GMD of the visual cortex in the control subjects and OAG patients. Spearman's rank correlation analysis was used to determine the relationship between optic nerve CSA and GMD in BA 17, 18, and 19. RESULTS: We found that the normal and OAG patients differed significantly in optic nerve CSA (p < 0.001) and visual cortex GMD in BA 17 (p = 0.030), BA 18 (p = 0.003), and BA 19 (p = 0.005). In addition, we found a significant correlation between optic nerve CSA and visual cortex GMD in BA 19 (r = 0.33, p = 0.023), but not in BA 17 (r = 0.17, p = 0.237) or BA 18 (r = 0.24, p = 0.099). CONCLUSION: Quantitative MRI parametric evaluation of GMD can detect glaucoma-associated anatomical atrophy of the visual cortex in BA 17, 18, and 19. Furthermore, GMD in BA 19 was significantly correlated to the damage level of the optic nerve, as well as the retina, in patients with OAG. This is the first demonstration of an association between the cortex of the brain responsible for higher-order visual function and glaucoma severity. Evaluation of the visual cortex with MRI is thus a very promising potential method for objective examination in OAG.

DOI： 10.1371/journal.pone.0197027

PubMed

The neuroprotective effect of hesperidin in NMDA-induced retinal injury acts by suppressing oxidative stress and excessive calpain activation Reviewed

Shigeto Maekawa, Kota Sato, Kosuke Fujita, Reiko Daigaku, Hiroshi Tawarayama, Namie Murayama, Satoru Moritoh, Takeshi Yabana, Yukihiro Shiga, Kazuko Omodaka, Kazuichi Maruyama, Koji M. Nishiguchi, Toru Nakazawa

Scientific Reports Vol. 7 ( 1 ) page： 6885 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

We found that hesperidin, a plant-derived bioflavonoid, may be a candidate agent for neuroprotective treatment in the retina, after screening 41 materials for anti-oxidative properties in a primary retinal cell culture under oxidative stress. We found that the intravitreal injection of hesperidin in mice prevented reductions in markers of the retinal ganglion cells (RGCs) and RGC death after N-methyl-D-aspartate (NMDA)-induced excitotoxicity. Hesperidin treatment also reduced calpain activation, reactive oxygen species generation and TNF-α gene expression. Finally, hesperidin treatment improved electrophysiological function, measured with visual evoked potential, and visual function, measured with optomotry. Thus, we found that hesperidin suppressed a number of cytotoxic factors associated with NMDA-induced cell death signaling, such as oxidative stress, over-activation of calpain, and inflammation, thereby protecting the RGCs in mice. Therefore, hesperidin may have potential as a therapeutic supplement for protecting the retina against the damage associated with excitotoxic injury, such as occurs in glaucoma and diabetic retinopathy.

DOI： 10.1038/s41598-017-06969-4

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Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7 Reviewed

Yukihiro Shiga, Japan Glaucoma Society Omics Group (JGS-OG), Koji M. Nishiguchi, Yosuke Kawai, Kaname Kojima, Kota Sato, Kosuke Fujita, Mai Takahashi, Kazuko Omodaka, Makoto Araie, Kenji Kashiwagi, Makoto Aihara, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Nobuo Fuse, Masayuki Yamamoto, Jun Yasuda, Masao Nagasaki, Toru Nakazawa

PLoS ONE Vol. 12 ( 12 ) page： e0186678 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science

Purpose To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis. Methods Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. Results Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P &lt
5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (? = -6.89 mmHg, P = 1.70E-04
dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (? = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (? = -2.16 and -2.82 ?m, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (? = 0.44 AU, P = 2.20E-02
additive model) and between GAS7 (rs9913911) and increased cup volume (? = 0.03 mm3, P = 4.60E-02) and mean cup depth (? = 0.03 mm3, P = 4.11E-02
additive model) and decreased pattern standard deviation (? = -0.87 dB, P = 2.44E-02
dominant model). Conclusion The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

DOI： 10.1371/journal.pone.0186678

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Papers - Koji Nishiguchi