MIYA Fuyuki

写真a

Affiliation

School of Medicine, Center for Medical Genetics （Shinanomachi）

Position

Associate Professor (Non-tenured)

External Links
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Academic Background 【 Display / hide 】

  • 2016.02

    University of Tsukuba, 人間総合科学研究科 疾患制御医学専攻

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（医学）, University of Tsukuba, Dissertation, 2016.02

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Papers 【 Display / hide 】

  • Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci.

    Yamaguchi K, Ishigaki K, Suzuki A, Tsuchida Y, Tsuchiya H, Sumitomo S, Nagafuchi Y, Miya F, Tsunoda T, Shoda H, Fujio K, Yamamoto K, Kochi Y

    Nature communications （Nature Communications)  13 （ 1 ） 4659 2022.08

    　View Summary

    Splicing quantitative trait loci (sQTLs) are one of the major causal mechanisms in genome-wide association study (GWAS) loci, but their role in disease pathogenesis is poorly understood. One reason is the complexity of alternative splicing events producing many unknown isoforms. Here, we propose two approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms. First, we integrate isoforms with the same coding sequence (CDS) and identify 369-601 integrated-isoform ratio QTLs (i2-rQTLs), which altered protein-structure, in six immune subsets. Second, we select CDS incomplete isoforms annotated in GENCODE and identify 175-337 isoform-ratio QTL (i-rQTL). By comprehensive long-read capture RNA-sequencing among these incomplete isoforms, we reveal 29 full-length isoforms with unannotated CDSs associated with GWAS traits. Furthermore, we show that disease-causal sQTL genes can be identified by evaluating their trans-eQTL effects. Our approaches highlight the understudied role of protein-altering sQTLs and are broadly applicable to other tissues and diseases.

  • Utility of tissue-specific gene expression scores for gene prioritization in Mendelian diseases.

    Kato D, Mitsuhashi S, Miya F, Saitoh S, Okamoto N, Tsunoda T, Kochi Y

    Journal of human genetics （Journal of Human Genetics)   2022.08

    ISSN  1434-5161

    　View Summary

    In genetic testing of Mendelian diseases, it is a bioinformatics challenge to effectively prioritize disease-causing candidate genes listed from massively parallel sequencing. Tissue specificity of the gene expression levels may give a clue because it may reflect tissue-specific disease manifestation. However, considering poor correlations between mRNA and protein expression in some genes, it is not clear whether transcriptomics- or proteomics-based tissue specificity should be used to prioritize candidate genes. Therefore, we compared the efficiency of tissue-specific scores (TS scores) obtained from transcriptome and proteome data in prioritizing candidate genes for whole exome sequencing (WES) analysis of Mendelian disease patients. We show that both Protein and RNA TS scores are useful in prioritizing candidate genes in WES analysis, although diseases like coagulopathies get more benefit from Protein TS score. This study may provide useful evidence in developing new methods to effectively identify novel disease-causing genes.

  • First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

    Takagi M, Ogawa C, Iehara T, Aoki-Nogami Y, Ishibashi E, Imai M, Kimura T, Nagata M, Yasuhara M, Masutani M, Yoshimura K, Tomizawa D, Ogawa A, Yonemori K, Morishita A, Miyamoto S, Takita J, Kihara T, Nobori K, Hasebe K, Miya F, Ikeda S, Shioda Y, Matsumoto K, Fujimura J, Mizutani S, Morio T, Hosoi H, Koike R

    Cancer （Cancer)  128 （ 15 ） 2949 - 2957 2022.08

    ISSN  0008-543X

    　View Summary

    Background: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. Methods: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3–18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Results: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. Conclusions: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. Lay summary: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

  • Deciphering complex rearrangements at the breakpoint of an apparently balanced reciprocal translocation t(4:18)(q31;q11.2)dn and at a cryptic deletion: Further evidence of TLL1 as a causative gene for atrial septal defect.

    Yamada M, Suzuki H, Miya F, Takenouchi T, Kosaki K

    American journal of medical genetics. Part A （American Journal of Medical Genetics, Part A)  188 （ 8 ） 2472 - 2478 2022.08

    ISSN  1552-4825

    　View Summary

    When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an “apparently balanced” de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7-Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Further analysis using a nanopore long-read sequencer showed complex rearrangements on both derivative chromosomes 4 and 18 and the deleted chromosome 2. First, the TLL1 locus, which is associated with atrial septal defect, was disrupted by the rearrangement involving chromosome 4. Second, the deleted interval at 2q31 included the entire HOXD cluster, the deletion of which is known to cause toe syndactyly, and the DLX1 and DLX2 loci, which are responsible for cleft lip and palate. Among the haplo-sensitive genes within the deleted interval on 2q31, only the RAPGEF4 gene is known to be associated with an autistic phenotype. Hence, most of the clinical features of the patient could be ascribed to specific genomic rearrangements. We have shown the effectiveness of long-read sequencing in defining, in detail, the likely effects of an apparently balanced translocation and cryptic deletion. The results of the present analysis suggest the possibility of phenotypic prediction through a detailed analysis of structural abnormalities, including balanced translocations and deletions.

  • De novo non-synonymous DPYSL2 (CRMP2) variants in two patients with intellectual disabilities and documentation of functional relevance through zebrafish rescue and cellular transfection experiments.

    Suzuki H, Li S, Tokutomi T, Takeuchi C, Takahashi M, Yamada M, Okuno H, Miya F, Takenouchi T, Numabe H, Kosaki K, Ohshima T

    Human molecular genetics  2022.07

    ISSN  0964-6906

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Reviews, Commentaries, etc. 【 Display / hide 】

  • GABRG2遺伝子変異を有するDravet症候群の1例

    原口 康平, 林田 拓也, 宮崎 あかね, 渡辺 麻美, 里 龍晴, 宮 冬樹, 加藤 光広, 森内 浩幸

    脳と発達 ((一社)日本小児神経学会)  54 ( Suppl. ) S322 - S322 2022.05

    ISSN  0029-0831

  • 精神運動発達遅滞を呈し脳波所見を契機にDNM1遺伝子変異による発達性てんかん性脳症と判明した女児例

    緒方 怜奈, 安永 由紀恵, 渡辺 恭子, 宮 冬樹, 加藤 光広

    脳と発達 ((一社)日本小児神経学会)  54 ( Suppl. ) S303 - S303 2022.05

    ISSN  0029-0831

  • 新生児期に洞停止を伴うてんかんと驚愕病で発症したSCN8A発達性てんかん性脳症の一例

    小路 梓, 中村 拓自, 一ノ瀬 文男, 宮 冬樹, 加藤 光広, 松尾 宗明

    脳と発達 ((一社)日本小児神経学会)  54 ( Suppl. ) S322 - S322 2022.05

    ISSN  0029-0831

  • synaptic vesicle protein 2A(SV2A)の遺伝子変異をもち、レベチラセタムで発作が増悪したミオクロニー失立発作てんかんの一例

    渡辺 麻美, 西口 菜奈子, 宮崎 あかね, 原口 康平, 里 龍晴, 宮 冬樹, 加藤 光広

    脳と発達 ((一社)日本小児神経学会)  54 ( Suppl. ) S322 - S322 2022.05

    ISSN  0029-0831

  • SCAF4変異による神経発達症と焦点性てんかんを認める1男児例

    中村 和幸, 安孫子 貴洋, 小林 信也, 三條 右京, 山本 志保, 阿部 暁子, 三井 哲夫, 宮 冬樹, 加藤 光広

    脳と発達 ((一社)日本小児神経学会)  54 ( Suppl. ) S272 - S272 2022.05

    ISSN  0029-0831

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • 脳オルガノイドを用いた巨脳症発症メカニズムの解明

    2020.04
    -
    2024.03

    日本学術振興会（科研費）, 基盤研究(B) , Research grant, Coinvestigator(s)

  • 人工知能 (AI) とRNA-Seqの融合による遺伝性小児神経疾患の新たな病態解明

    2020.04
    -
    2023.03

    日本学術振興会（科研費）, 基盤研究(C) , Research grant, Coinvestigator(s)

  • 神経・筋相互作用を標的とした運動神経疾患の病態解明と治療開発

    2020.04
    -
    2023.03

    日本医療研究開発機構（AMED）,  疾患特異的iPS細胞の利活用促進・難病研究加速プログラム, Commissioned ｒesearch, Coinvestigator(s)

  • 小児視覚聴覚二重障害の分子遺伝学的研究

    2018.04
    -
    2020.03

    日本医療研究開発機構（AMED）, 難治性疾患実用化研究事業, Commissioned ｒesearch, Coinvestigator(s)

  • 網膜色素変性症に対する遺伝子特異的治療実現を目的とした、集約的遺伝解析とゲノム編集技術による病態解明

    2017.04
    -
    2020.03

    日本医療研究開発機構（AMED）, 難治性疾患実用化研究事業, Commissioned ｒesearch, Coinvestigator(s)

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