Takenouchi, Toshiki

写真a

Affiliation

School of Medicine, Department of Pediatrics (Shinanomachi)

Position

Assistant Professor/Senior Assistant Professor

External Links

Academic Background 【 Display / hide

  • 1996.04
    -
    2002.03

    Keio University, 医学部

    University, Graduated

Academic Degrees 【 Display / hide

  • 博士(医学), 慶應義塾大学

Licenses and Qualifications 【 Display / hide

  • American Board of Psychiatry and Neurology, 2009.09

  • American Board of Pediatrics, 2009.10

  • 日本小児科専門医, 2011.10

  • 日本臨床遺伝専門医, 2012.11

  • 日本小児神経専門医, 2012.11

 

Research Areas 【 Display / hide

  • Life Science / Embryonic medicine and pediatrics

 

Books 【 Display / hide

  • Intraventricular hemorrhage and white matter injury in the preterm infant

    Takenouchi Toshiki, Perlman Jeffrey M., 2012

Papers 【 Display / hide

  • Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

    Harigai Ritsuko, Sakai Shigeki, Nobusue Hiroyuki, Hirose Chikako, Sampetrean Oltea, Minami Noriaki, Hata Yukie, Kasama Takashi, Hirose Takanori, Takenouchi Toshiki, Kosaki Kenjiro, Kishi Kazuo, Saya Hideyuki, Arima Yoshimi

    Scientific Reports 8 ( 1 )  2018.12

    Research paper (scientific journal),  ISSN  2045-2322

     View Summary

    <p>Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.</p>

  • Expanding Phenotype of Nephronophthisis-Related Ciliopathy

    Kawaguchi Takahisa, Yoshida Tadashi, Hirahashi Junichi, Uehara Tomoko, Takenouchi Toshiki, Kosaki Kenjiro, Itoh Hiroshi, Hayashi Matsuhiko

    Nephron    1 - 5 2018.07

    Research paper (scientific journal), Accepted,  ISSN  1660-8151

     View Summary

    <p>Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G&gt;A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.</p>

  • Growth pattern of Rahman syndrome

    Takenouchi Toshiki, Uehara Tomoko, Kosaki Kenjiro, Mizuno Seiji

    American Journal of Medical Genetics, Part A 176 ( 3 ) 712 - 714 2018.03

    Research paper (scientific journal), Accepted,  ISSN  1552-4825

     View Summary

    <p>Recently, in a cohort study with “overgrowth syndrome with intellectual disability,” five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones. She did not exhibit skeletal overgrowth, but she had a short stature at 21 years of age. An exome analysis identified a de novo heterozygous 1-bp duplication in HIST1H1E, that is, c.433dup p.(Ala145Glyfs*51). The physical features of the proposita were essentially the same as those observed in patients with the aforementioned HIST1H1E-related overgrowth syndrome. Our review of the growth trajectories in seven patients showed that five of seven patients did not exhibit skeletal overgrowth. This “lack of overgrowth in overgrowth syndrome” is reminiscent of a subset of patients with a short stature who have Sotos syndrome, a prototypic overgrowth syndrome. Considering this complexity in growth, this newly identified condition should be referred to as Rahman syndrome.</p>

  • Three patients with DeSanto-Shinawi syndrome

    Uehara Tomoko, Ishige Takashi, Hattori Shigeto, Yoshihashi Hiroshi, Funato Michinori, Yamaguchi Yu, Takenouchi Toshiki, Kosaki Kenjiro

    American Journal of Medical Genetics, Part A  2018.01

    Research paper (scientific journal), Accepted,  ISSN  1552-4825

     View Summary

    <p>Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants.</p>

  • Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants

    Uehara Tomoko, Takenouchi Toshiki, Kosaki Rika, Kurosawa Kenji, Mizuno Seiji, Kosaki Kenjiro

    European Journal of Medical Genetics  2018.01

    ISSN  1769-7212

     View Summary

    <p>Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G &gt; A, p.Gly717Arg mutation, and one had a c.2525A &gt; G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.</p>

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Papers, etc., Registered in KOARA 【 Display / hide

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

  • Metagenomic analysis of tissues and body fluids in neonatal hepatitis and encephalitis

    2022.06
    -
    2025.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究(萌芽), Principal investigator

  • PDGFRB異常による新規過成長症候群の病態解明と治療法開発

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • CDC42遺伝子異常症の病態解明

    2016.04
    -
    2019.03

    Grant-in-Aid for Scientific Research, Research grant, Principal investigator

  • 新生児低酸素性虚血性脳症に対する低体温療法の至適化のための包括的代謝解析の研究

    2014.04
    -
    2016.03

    Research grant, Principal investigator

  • 顕微質量分析による新生児低酸素性脳症の代謝システムの制御解明と低体温療法の最適化

    2012.04
    -
    2014.03

    Grant-in-Aid for Scientific Research, Research grant, Principal investigator

Awards 【 Display / hide

  • 日本医師会医学研究奨励賞

    2016

    Type of Award: Award from publisher, newspaper, foundation, etc.

  • 三四会奨励賞

    2015

  • 森永奉仕会研究奨励金特別賞太田敬三記念賞

    2013

    Type of Award: Award from publisher, newspaper, foundation, etc.

 

Courses Taught 【 Display / hide

  • MEDICAL PROFESSIONALISM 6

    2024

  • LECTURE SERIES, PEDIATRICS

    2024

  • LECTURE SERIES, PEDIATRICS

    2023

  • LECTURE SERIES, PEDIATRICS

    2022

  • LECTURE SERIES, PEDIATRICS

    2021

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Courses Previously Taught 【 Display / hide

  • 小児科学系統講義

    Keio University

    2018.04
    -
    2019.03

    Full academic year, Lecture

  • メディカルプロフェッショナリズム

    Keio University

    2018.04
    -
    2019.03

    Full academic year, Lecture

 

Memberships in Academic Societies 【 Display / hide

  • 日本小児科学会

     
  • 日本小児神経学会

     
  • 日本人類遺伝学会

     
  • 日本小児遺伝学会

     

Committee Experiences 【 Display / hide

  • 2014.09
    -
    Present

    将来の小児科医を考える委員会, 日本小児科学会