Papers - IKEDA Yasuhiro
-
Murakami Y., Koyanagi Y., Fukushima M., Yoshimura M., Fujiwara K., Akiyama M., Momozawa Y., Ueno S., Terasaki H., Oishi A., Miyata M., Ikeda H., Tsujikawa A., Mizobuchi K., Hayashi T., Fujinami K., Tsunoda K., Park J.Y., Han J., Kim M., Lee C.S., Kim S.J., Park T.K., Joo K., Woo S.J., Ikeda Y., Sonoda K.H.
Ophthalmology Retina 5 ( 12 ) 1269 - 1279 2021.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Ophthalmology Retina
Purpose: To investigate the genotype and long-term clinical phenotype of patients with Bietti crystalline dystrophy (BCD) in Korea and Japan. Design: Retrospective case series. Participants: We analyzed 62 patients with clinical features of BCD who harbor pathogenic biallelic CYP4V2 variants in their homozygote or compound heterozygote. Methods: Data were collected from patient charts, including age, best-corrected visual acuity (BCVA), Goldmann perimetry results, fundus photography, OCT findings, fundus autofluorescence results, and electroretinography findings. We compared the clinical course of the patients with homozygous c.802-8_810de117insGC [exon7del], the most common mutation in the East Asian population, with those of the patients with other genotypes. Main Outcome Measures: Best-corrected visual acuity, visual field (VF), and their changes during follow-up. Results: The mean age at the first visit was 55.2 years, with a mean follow-up of 7.1 years. The mean BCVAs at the first and last visits were 0.28 logarithm of the minimum angle of resolution (logMAR) and 0.89 logMAR, respectively. In genetic testing, c.802-8_810de117insGC was detected in 86 of 124 alleles of the patients, and 36 patients were homozygous for this mutation. The age, BCVA, VF area, central foveal thickness, and abnormal hypoautofluorescent area at either the first or last visit were not different between the exon7del homozygotes and the others. The mean BCVA changes per year were 0.089 logMAR in the exon7del homozygotes and 0.089 logMAR in the others. An age- and gender-adjusted linear regression analysis showed no association between the exon7del homozygote status and the rate of vision loss. Characteristic crystalline deposits in the posterior pole were generally observed in younger patients and disappeared over time along with progressive retinochoroidal atrophy. Conclusions: Patients with BCD and a homozygote for c.802-8_810de117insGC accounted for more than 50% of this cohort of Korean and Japanese patients, and the clinical effect of this deleterious variant was not severe in the spectrum of CYP4V2 retinopathy.
-
Nishiguchi K.M., Miya F., Mori Y., Fujita K., Akiyama M., Kamatani T., Koyanagi Y., Sato K., Takigawa T., Ueno S., Tsugita M., Kunikata H., Cisarova K., Nishino J., Murakami A., Abe T., Momozawa Y., Terasaki H., Wada Y., Sonoda K.H., Rivolta C., Tsunoda T., Tsujikawa M., Ikeda Y., Nakazawa T.
Communications Biology 4 ( 1 ) 140 2021.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Communications Biology
The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10−8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.
-
特集 網膜色素変性のアップデート 【治療法開発研究の最前線】 網膜色素変性に対する遺伝子治療 Invited
池田 康博
臨床眼科 75 ( 12 ) 1475 - 1482 2021.11
Authorship：Lead author, Corresponding author Language：Japanese Publishing type：Part of collection (book) Publisher：株式会社医学書院
-
Genetic and phenotypic landscape of PRPH2-associated retinal dystrophy in Japan Reviewed
Oishi A., Fujinami K., Mawatari G., Naoi N., Ikeda Y., Ueno S., Kuniyoshi K., Hayashi T., Kondo H., Mizota A., Shinoda K., Kusuhara S., Nakamura M., Iwata T., Tsujikawa A., Tsunoda K.
Genes 12 ( 11 ) 2021.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Genes
Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.
-
Regional differences in genes and variants causing retinitis pigmentosa in Japan Reviewed
Koyanagi Y., Akiyama M., Nishiguchi K.M., Momozawa Y., Kamatani Y., Takata S., Inai C., Iwasaki Y., Kumano M., Murakami Y., Komori S., Gao D., Kurata K., Hosono K., Ueno S., Hotta Y., Murakami A., Terasaki H., Wada Y., Nakazawa T., Ishibashi T., Ikeda Y., Kubo M., Sonoda K.H.
Japanese Journal of Ophthalmology 65 ( 3 ) 338 - 343 2021.5
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
Purpose: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan Study design: Retrospective multicenter study Methods: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. Results: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P =.99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. Conclusion: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.
-
Gene therapy for patients with retinitis pigmentosa Reviewed
Ikeda Y.
Japanese Journal of Clinical Ophthalmology 75 ( 12 ) 1475 - 1482 2021
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Clinical Ophthalmology
-
Effect of Topical Dorzolamide on Cystoid Macular Edema in Retinitis Pigmentosa. Reviewed
Shimokawa S, Fujiwara K, Murakami Y, Funatsu J, Nakatake S, Yoshida N, Sonoda KH, Ikeda Y.
Ophthalmol Retina 4 ( 10 ) 1036 - 1039 2020.10
Language：English Publishing type：Research paper (other academic) Publisher：Ophthalmology Retina
-
Okita A., Murakami Y., Shimokawa S., Funatsu J., Fujiwara K., Nakatake S., Koyanagi Y., Akiyama M., Takeda A., Hisatomi T., Ikeda Y., Sonoda K.H.
Investigative ophthalmology & visual science 61 ( 11 ) 30 2020.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative ophthalmology & visual science
Purpose: Retinal degeneration involves neuroinflammation, and pro-inflammatory cytokines/chemokines are markedly increased in the eyes of patients with retinitis pigmentosa (RP). In this study, we investigated the changes of serum cytokines/chemokines in RP, and their relationships with visual parameters. Methods: Forty-five consecutive patients with typical RP aged 20 to -39 years and 28 age-matched and gender-matched controls were included. Fifteen cytokines (interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, 1L-15, IL-17, IL-23, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α, TNF-β) and 9 chemokines (eotaxin, growth-related oncogene [GRO]-α, I-309, IL-8, IFN-γ-inducible protein [IP]-10, monocyte chemotactic protein [MCP]-1, MCP-2, regulated activation normal T-cell expressed and secreted [RANTES], and thymus and activated regulated chemokine [TARC]) in the serum were simultaneously measured by a multiplexed immunoarray (Q-Plex). Relationships between these cytokines/chemokines and indices of central vision, such as visual acuity (VA), the values of static perimetry tests (Humphrey Field analyzer, the central 10-2 program), and optical coherence tomography measures were analyzed in the patients with RP. Results: Among the 15 cytokines and 9 chemokines, serum IL-8 and RANTES levels were significantly increased in patients with RP compared with controls (IL-8: P < 0.0001; RANTES: P < 0.0001). Among the elevated cytokines/chemokines, the levels of IL-8 were negatively correlated with VA (ρ = 0.3596 and P = 0.0165), and the average retinal sensitivity of four central points (ρ = -0.3691 and P = 0.0291), and 12 central points (ρ = -0.3491 and P = 0.0398), as well as the central subfield thickness (ρ = -0.3961 and P = 0.0094), and ellipsoid zone width (ρ = -0.3841 and P = 0.0120). Conclusions: Peripheral inflammatory response may be activated and serum IL-8 levels are associated with central vision in patients with RP.
-
Koyanagi Y., Ueno S., Ito Y., Kominami T., Komori S., Akiyama M., Murakami Y., Ikeda Y., Sonoda K.H., Terasaki H.
Investigative Ophthalmology and Visual Science 61 ( 10 ) 6 2020.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
Copyright 2020 The Authors. PURPOSE. To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). METHODS. We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch’s membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/μm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. RESULTS. The median MMCI was -31.2 × 10-5/μm for the RPGR eyes, -16.5 × 10-5/μm for the RP1L1 eyes, -13.0 × 10-5/μm for the RP1 eyes, -9.8 × 10-5/μm for the EYS eyes, and -9.0 × 10-5/μm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10-6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). CONCLUSIONS. The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes.
DOI： 10.1167/IOVS.61.10.6
-
Nishiguchi K.M., Kunikata H., Fujita K., Hashimoto K., Koyanagi Y., Akiyama M., Ikeda Y., Momozawa Y., Sonoda K.H., Murakami A., Wada Y., Nakazawa T.
Clinical and Experimental Ophthalmology 48 ( 5 ) 644 - 657 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical and Experimental Ophthalmology
© 2020 Royal Australian and New Zealand College of Ophthalmologists Importance: A framework for understanding the phenotypic features of CRX retinopathy was established. Background: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. Design: Multicentre retrospective study. Participants: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. Methods: Retrospective data analysis. Main Outcome Measures: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). Results: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. Conclusions and Relevance: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes.
DOI： 10.1111/ceo.13743
-
A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa Reviewed
Nishiguchi K.M., Fujita K., Ikeda Y., Kunikata H., Koyanagi Y., Akiyama M., Abe T., Wada Y., Sonoda K.H., Nakazawa T.
Japanese Journal of Ophthalmology 64 ( 4 ) 346 - 350 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
© 2020, Japanese Ophthalmological Society. Purpose: To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene. Study design: Prospective, clinical and experimental study. Methods: The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed. Results: Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect. Conclusion: The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.
-
Aqueous flare and progression of visual field loss in patients with retinitis pigmentosa Reviewed
Fujiwara K., Ikeda Y., Murakami Y., Tachibana T., Funatsu J., Koyanagi Y., Nakatake S., Shimokawa S., Yoshida N., Nakao S., Hisatomi T., Ishibashi T., Sonoda K.H.
Investigative Ophthalmology and Visual Science 61 ( 8 ) 26 2020.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2020 The Authors. PURPOSE. To investigate the association between aqueous flare and progression of visual field loss using the Humphrey Field Analyzer in patients with retinitis pigmentosa (RP). METHODS. We examined a total of 101 eyes of 101 patients who were diagnosed with typical RP. Sixty-one percent of the patients were female, and the mean age of the total group was 47.4 years. Aqueous flare, visual field (by an Humphrey Field Analyzer, the central 10-2 SITA-Standard program), and optical coherence tomography measurements were obtained for all patients. The slope, which was derived from serial values of mean deviation, macular sensitivity, or foveal sensitivity for each eye with univariate linear regression, was used for analysis. RESULTS. Aqueous flare values were significantly correlated with the mean deviation slope (r =-0.20, P = 0.046), macular sensitivity slope (r =-0.28, P = 0.005) and foveal sensitivity slope (r =-0.20, P = 0.047). The values of the retinal sensitivity slope significantly decreased as the aqueous flare level increased (all P < 0.05). These associations remained unchanged after adjustment for age, sex, and posterior subcapsular cataract, and epiretinal membrane. CONCLUSIONS. Elevation of aqueous flare is a risk factor for the decline of central visual function in RP. Aqueous flare may be a useful marker for disease progression in RP.
DOI： 10.1167/IOVS.61.8.26
-
Shimokawa S., Nakao S., Murakami Y., Ikeda Y., Sonoda K.H.
American Journal of Ophthalmology Case Reports 18 100682 2020.6
Language：Japanese Publishing type：Case report Publisher：American Journal of Ophthalmology Case Reports
Purpose: Two diabetic case reports of serous retinal detachment (SRD) accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for neovascular glaucoma (NVG). Observations: Case 1: A 66-year-old female with stage 3 NVG and decreased vision acuity in the left eye. After trabeculectomy, postoperative laser suture lysis (LSL) resulted in development of hypotony maculopathy, followed by pachychoroid and SRD. Injection of C3F8 gas in the anterior chamber was unsuccessful and transconjunctival scleral re-suturing was performed. Intraocular pressure (IOP) consequently increased and SRD improved. Case 2: A 60-year-old man with stage 2 NVG and decreased vision acuity in the right eye. Trabeculectomy was uneventful, but postoperative LSL also resulted in development of hypotony maculopathy followed by pachychroid and SRD. Intravitreal bevacizumab injection had no effect and transconjunctival flap re-suturing was performed. IOP consequently increased and SRD improved. Conclusions: SRD accompanied by pachychoroid was observed in hypotony maculopathy in diabetic cases. VEGF-independent exudative change in hypotony maculopathy may be due to hydrostatic pressure elevation in choroidal blood vessels based on Starling's hypothesis with the consequent breakdown of retinal pigment epithelium barrier in diabetic patients.
-
Serous retinal detachment accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for diabetic neovascular glaucoma. Reviewed
Shimokawa S, Nakao S, Murakami Y, Ikeda Y, Sonoda KH.
Am J Ophthalmol Case Rep 2020.3
Language：English Publishing type：Research paper (other academic)
-
Sakamoto T., Kawano S., Kawasaki R., Hirakata A., Yamashita H., Yamamoto S., Ishibashi T., Sato E., Kitahashi M., Tatsumi T., Miura G., Niizawa T., Yamakiri K., Yamashita T., Otsuka H., Sameshima S., Yoshinaga N., Sonoda S., Koto T., Inoue M., Hirota K., Itoh Y., Orihara T., Emoto Y., Sano M., Takahashi H., Tokizawa R., Nishitsuka K., Kaneko Y., Nishi K., Yoshida A., Ono S., Hirokawa H., Sogawa K., Omae T., Ishibazawa A., Kishi S., Akiyama H., Matsumoto H., Mukai R., Morimoto M., Nakazawa M., Suzuki Y., Kudo T., Adachi K., Ishida S., Noda K., Kase S., Mori S., Ando R., Saito M., Suzuki T., Takahashi K., Nagai Y., Nakauchi T., Yamada H., Kusaka S., Tsujioka D., Tsujikawa A., Suzuma K., Sonoda K.H., Ikeda Y., Kohno R., Ishikawa K., Kondo M., Kozawa M., Kitaoka T., Tsuiki E., Ogura Y., Yoshida M., Morita H., Kato A., Hirano Y., Sugitani K., Terasaki H., Iwase T., Ito Y., Ueno S., Kaneko H., Nonobe N., Kominami T., Azuma N., Yokoi T., Shimada H., Nakashizuka H., Hattori T., Shinojima A., Kutagawa Y., Shiraga F., Morizane Y., Kimura S., Ikeda T., Kida T., Sato T., Fukumoto M., Emi K., Nakashima H., Ohji M., Kakinoki M.
Japanese Journal of Ophthalmology 64 ( 1 ) 1 - 12 2020.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
Purpose: To report the demographics and clinical characteristics of patients with a primary retinal detachment (RD). Design: Prospective cohort study by a registry design. Participants: Patients with RD treated at vitreoretinal sub-specialty institutions in Japan from February 2016 to March 2017. Methods: Descriptive statistics for the primary RD, and multivariable ordered logistic regression and multiple linear regression analyses were performed. Results: 3178 eyes of 3178 cases were analyzed. The interval from onset to surgery was significantly shorter in patients in the 40-year age group than in other age groups except for the 50-year age group (P<0.05, Steel-Dwass test). The proportion of complex cases was significantly higher in the 10-year, 70-year, and 80+ year age groups than in the 40 and 50-year age groups (P<0.05, Steel-Dwass test). The size of RD was significantly associated with the male sex (odds ratio, 1.29; 95% confidence interval [CI], 1.07 to 1.56; P=0.0085) and the interval from onset to surgery (odds ratio, 1.03 95% CI, 1.01 to 1.04; P=0.0014). Low IOPs in eyes with RD were significantly associated with an older age (-0.24 mmHg/10 years, 95% CI, -0.32 to -0.16], P<0.0001) and larger RD area (-0.91 mmHg/quadrant, 95% CI, [-1.06 to -0.76], P <0.0001). Conclusion: Profile and clinical characteristics of patients with a primary RD were not exactly the same as previous reports. A preoperative low IOP was associated with several ocular factors while the area of RD was associated not only with ocular but with social factors as well.
-
Direct comparison of retinal structure and function in retinitis pigmentosa by co-registering microperimetry and optical coherence tomography. Reviewed
Funatsu J, Murakami Y, Nakatake S, Akiyama M, Fujiwara K, Shimokawa S, Tachibana T, Hisatomi T, Koyanagi Y, Momozawa Y, Sonoda KH, Ikeda Y.
PLoS One. 2019.12
Language：English Publishing type：Research paper (scientific journal)
-
Nikopoulos K., Cisarova K., Quinodoz M., Koskiniemi-Kuendig H., Miyake N., Farinelli P., Rehman A., Khan M., Prunotto A., Akiyama M., Kamatani Y., Terao C., Miya F., Ikeda Y., Ueno S., Fuse N., Murakami A., Wada Y., Terasaki H., Sonoda K., Ishibashi T., Kubo M., Cremers F., Kutalik Z., Matsumoto N., Nishiguchi K., Nakazawa T., Rivolta C.
Nature Communications 10 ( 1 ) 2019.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications
© 2019, The Author(s). 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.
-
Kaizu Y., Nakao S., Arima M., Hayami T., Wada I., Yamaguchi M., Sekiryu H., Ishikawa K., Ikeda Y., Sonoda K.
Scientific Reports 9 ( 1 ) 2019.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
© 2019, The Author(s). Our study evaluated the diagnostic capability of flow density (FD) in OCT angiography (OCTA) for diabetic retinopathy (DR) detection in diabetic patients. We studied 93 eyes of 68 diabetic patients who underwent OCTA (36 and 57 eyes without and with DR, respectively). Retinal capillary FD of a 2.6 × 2.6 mm2 area and four divided areas at the superficial (SCP) and deep capillary plexus (DCP) were measured. Predictions were evaluated using the area under the receiver operating characteristic curve (AUC). The diagnostic capabilities of the FDs in discriminating between eyes without DR and eyes with total or early DR were compared. Furthermore, predictions with foveal avascular zone (FAZ) area, hemoglobin A1c (HbA1c), and DM duration were also compared with FD. Prediction using FD AUC in the temporal side in the DCP (0.83) was the highest and significantly better than all other AUCs examined (P < 0.05), including discriminating between eyes without DR and with early DR (P < 0.01). Prediction using this particular AUC was also significantly better than that by FAZ area and HbA1c (P < 0.001 and <0.001, respectively). Area-divided FD in OCTA may be valuable for diagnosing retinopathy in diabetic patients.
-
Notomi S, Ishihara K, Efstathiou NE, Lee JJ, Hisatomi T, Tachibana T, Konstantinou EK, Ueta T, Murakami Y, Maidana DE, Ikeda Y, Kume S, Terasaki H, Sonoda S, Blanz J, Young L, Sakamoto T, Sonoda KH, Saftig P, Ishibashi T, Miller JW, Kroemer G, Vavvas DG.
Proc Natl Acad Sci U S A. 116 ( 47 ) 23724 - 23734 2019.11
Language：English Publishing type：Research paper (scientific journal)
© 2019 National Academy of Sciences. All rights reserved. The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/ phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
-
Ishizu M., Murakami Y., Fujiwara K., Funatsu J., Shimokawa S., Nakatake S., Tachibana T., Hisatomi T., Koyanagi Y., Akiyama M., Momozawa Y., Ishibashi T., Sonoda K.H., Ikeda Y.
Investigative Ophthalmology and Visual Science 60 ( 13 ) 4462 - 4468 2019.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
Copyright 2019 The Authors PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.