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Pathogenesis of phenotypic heterogeneity in MAP3K7 related disorders

Research Project

Project/Area Number 20K09916
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57020:Oral pathobiological science-related
Research InstitutionNational Center for Child Health and Development

Principal Investigator

Yanagi Kumiko  国立研究開発法人国立成育医療研究センター, ゲノム医療研究部, 研究員 (90294701)

Co-Investigator(Kenkyū-buntansha) 要 匡  国立研究開発法人国立成育医療研究センター, ゲノム医療研究部, 部長 (40264288)
石谷 太  大阪大学, 微生物病研究所, 教授 (40448428)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords心脊椎手根骨顔症候群 / 前頭・骨幹端異形成症 / MAP3K7 / 単一遺伝性疾患 / 表現型異質性 / 網羅的遺伝学的解析 / 特異的顔貌 / 心脊椎手根骨顔症候群(CSCF) / 前頭・骨幹端異形成症(FMD) / ゼブラフィッシュ / 先天奇形疾患 / 頭・骨幹端異形成症
Outline of Research at the Start

網羅的な遺伝学的解析が可能となってきた現在、臨床的に同一疾患であっても原因となる遺伝子座位が異なる場合(表現型異質性)や、遺伝子座位が同じであっても臨床的には別疾患と診断される場合(表現型異質性)など、いわゆる単一遺伝性疾患でさえも遺伝性疾患の分子病態はより多様、複雑であることが明らかになりつつある。本研究ではMAP3K7遺伝子変異が原因とされる表現型が全く異なる2つの遺伝性疾患、心脊椎手根骨顔症候群(CSCF)と前頭・骨幹端異形成症(FMD)疾患の表現型異質性について細胞およびモデル動物(ゼブラフィッシュ)を用いて分子病態を検証し、遺伝学的背景に基づいた説明を試みる。

Outline of Final Research Achievements

MAP3K7 is known as a causative gene for cardiospinocarpal facies syndrome (CSCF) which is characterized by cardiac abnormalities, carpal fusion, and dysmorphic facial appearance. In this study, we identified a novel pathogenic variant of MAP3K7 (p.Ser192Gly)and analysed its function.
In silico analysis predicted that the variant would result in the loss of the phosphorylation site, and attenuation of its autophosphorylation was confirmed by in vitro analysis. In zebrafish in which MAP3K7 was selectively suppressed with MAP3K7 inhibitors or morpholino, the number of individuals with a CSCF-like phenotype was significantly increased. Peripheral blood cells obtained from the CSCF patient had reduced cell adhesion to MAP3K7 stimulation. We also identified a novel frameshift variant in TAB2 which formed a complex with MAP3K7 in patients with CSCF-like phenotype. These results suggested that loss of function of the MAP3K7 pathway might be involved in the CSCF-like phenotype.

Academic Significance and Societal Importance of the Research Achievements

本研究により、心室中隔欠損、手根骨癒合、特異的な顔貌、歯の放出遅延などのCSCFの表現型発現にMAP3K7の機能喪失型バリアントが関与していることがin vitroやin vivoでの解析を通じて明確に示すことができた。加えて、CSCF様の表現型を呈する別の症例でMAP3K7と複合体を形成するTAB2に新規のフレームシフトバリアントを同定されたことは、MAP3K7を中心とする機能喪失型のシグナルカスケードがCSCF類似の表現型に関与することを示唆しており、あらたな疾患概念の提唱につながる可能性が高く、学術的にも意義のある発見となった。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (33 results)

All 2023 2022 2021 2020

All Journal Article (23 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 23 results,  Open Access: 6 results) Presentation (10 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Clinical characteristics of muscle cramps in hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome associated with a novel COL4A1 pathogenic variant: A family case study2023

    • Author(s)
      Haga Shunsuke、Takeguchi Ryo、Tanaka Ryosuke、Satake Akira、Makita Yoshio、Yanagi Kumiko、Kaname Tadashi、Takahashi Satoru
    • Journal Title

      Brain and Development

      Volume: - Issue: 7 Pages: 390-394

    • DOI

      10.1016/j.braindev.2023.02.008

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biallelic CC2D2A variants, SNV and LINE-1 insertion simultaneously identified in siblings using long-read whole-genome sequencing and haplotype phasing2023

    • Author(s)
      Yanagi Kumiko、Coker Jonathan、Miyana Kaori、Aso Seijiro、Kobayashi Nana、Satou Kazuhito、Richman Adam、Indupuru Suneel、Matsubara Yoichi、Kaname Tadashi
    • Journal Title

      Journal of Human Genetics

      Volume: - Issue: 6 Pages: 431-435

    • DOI

      10.1038/s10038-023-01130-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Additional findings of tibial dysplasia in a male with orofaciodigital syndrome type XVI2022

    • Author(s)
      Chinen Yasutsugu、Nakamura Sadao、Yanagi Kumiko、Kaneshi Takuya、Goya Hideki、Yoshida Tomohide、Satou Kazuhito、Kaname Tadashi、Naritomi Kenji、Nakanishi Koichi
    • Journal Title

      Human Genome Variation

      Volume: 9 Issue: 1

    • DOI

      10.1038/s41439-022-00187-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The novel and recurrent variants in exon 31 of CREBBP in Japanese patients with Menke-Hennekam syndrome2022

    • Author(s)
      Nishi E, Takenouchi T, Miya F, Uehara T, Yanagi K, Hasegawa Y, Ueda K, Mizuno S, Kaname T, Kosaki K, Okamoto N
    • Journal Title

      Am J Med Genet A

      Volume: 188 Issue: 2 Pages: 446-453

    • DOI

      10.1002/ajmg.a.62533

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 152021

    • Author(s)
      Ueda K, Ogawa S, Matsuda K, Hasegawa Y, Nishi E, Yanagi K, Kaname T, Yamamoto T, Okamoto N.
    • Journal Title

      Am J Med Genet A

      Volume: 185 Issue: 10 Pages: 3092-3098

    • DOI

      10.1002/ajmg.a.62371

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Deep intronic deletion in intron 3 of PLP1 is associated with a severe phenotype of Pelizaeus-Merzbacher disease2021

    • Author(s)
      Yamamoto-Shimojima Keiko、Akagawa Hiroyuki、Yanagi Kumiko、Kaname Tadashi、Okamoto Nobuhiko、Yamamoto Toshiyuki
    • Journal Title

      Human Genome Variation

      Volume: 8 Issue: 1 Pages: 14-14

    • DOI

      10.1038/s41439-021-00144-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Four pedigrees with aminoacyl-tRNA synthetase abnormalities2021

    • Author(s)
      Okamoto Nobuhiko、Miya Fuyuki、Tsunoda Tatsuhiko、Kanemura Yonehiro、Saitoh Shinji、Kato Mitsuhiro、Yanagi Kumiko、Kaname Tadashi、Kosaki Kenjiro
    • Journal Title

      Neurological Sciences

      Volume: 43 Issue: 4 Pages: 2765-2774

    • DOI

      10.1007/s10072-021-05626-z

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021

    • Author(s)
      Hiraide T, Yamoto K, Masunaga Y, Asahina M, Endoh Y, Ohkubo Y, Matsubayashi T, Tsurui S, Yamada H, Yanagi K, Nakashima M, Hirano K, Sugimura H, Fukuda T, Ogata T, Saistu T
    • Journal Title

      Clin Genet

      Volume: 100 Issue: 1 Pages: 40-50

    • DOI

      10.1111/cge.13951

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Successful kidney transplantation in a patient with neonatal-onset ILNEB2021

    • Author(s)
      Okamoto T, Nakamura A, Hayashi A, Yamaguchi T, Ogawa Y, Natsuga K, Yanagi K, Hotta K
    • Journal Title

      Pediatr Transplant

      Volume: 25 Issue: 5

    • DOI

      10.1111/petr.13971

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] HECW2-related disorder in four Japanese patients2021

    • Author(s)
      Yanagishita T, Hirade T, Shimojima Yamamoto K, Funatsuka M, Miyamoto Y, Maeda M, Yanagi K, Kaname T, Nagata S, Nagata M, Ishihara Y, Miyashita Y, Asano Y, Sakata Y, Kosaki K, Yamamoto T
    • Journal Title

      Am Med Genet A

      Volume: 185 Issue: 10 Pages: 2895-2902

    • DOI

      10.1002/ajmg.a.62363

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] GFAP variant p.Tyr366Cys demonstrated widespread brain cavitation in neonatal Alexander disease2021

    • Author(s)
      Takeuchi H, Higurashi N, Kawame H, Kaname T, Yanagi K, Nonaka Y, Hirotsu T, Matsushima S, Shimizu T, Gomi T, Fukasawa N
    • Journal Title

      Radiol Case Rep

      Volume: 17 Issue: 3 Pages: 771-774

    • DOI

      10.1016/j.radcr.2021.11.066

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Two types of early epileptic encephalopathy in a Pitt-Hopkins syndrome patient with a novel TCF4 mutation2021

    • Author(s)
      Kirikae H, Uematsu M, Numata-Uematsu Y, Saijo N, Katata Y, Oikawa Y, Kikuchi A, Yanagi K, Kaname T, Haginoya K, Kure S
    • Journal Title

      Brain Dev

      Volume: 44 Issue: 2 Pages: 148-152

    • DOI

      10.1016/j.braindev.2021.09.003

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] ETV6-related thrombocytopenia associated with a transient decrease in von Willebrand factor2021

    • Author(s)
      Kanamaru Yuri、Uchiyama Toru、Kaname Tadashi、Yanagi Kumiko、Ohara Osamu、Kunishima Shinji、Ishiguro Akira
    • Journal Title

      International Journal of Hematology

      Volume: - Issue: 2 Pages: 297-300

    • DOI

      10.1007/s12185-021-03136-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND12021

    • Author(s)
      Yanagi K, Morimoto N, Iso M, Abe Y, Okamura K, Nakamura T, Matsubara Y, Kaname T
    • Journal Title

      J Hum Genet

      Volume: - Issue: 10 Pages: 1029-1034

    • DOI

      10.1038/s10038-021-00915-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] X-linked mental retardation and severe short stature with a novel mutation of the <i>KDM5C</i> gene2021

    • Author(s)
      Kawano-Matsuda F, Maeda T, Kaname T, Yanagi K, Ihara K
    • Journal Title

      Clinical Pediatric Endocrinology

      Volume: 30 Issue: 1 Pages: 61-64

    • DOI

      10.1297/cpe.30.61

    • NAID

      130007966051

    • ISSN
      0918-5739, 1347-7358
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.2021

    • Author(s)
      Zarate YA, Uehara T, Kaname T, Ishitani T, Kosaki K. et. al.
    • Journal Title

      Genet Med.

      Volume: - Issue: 6 Pages: 1050-1057

    • DOI

      10.1038/s41436-020-01091-9

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] <i>NT5E</i> Genetic Mutation Is a Rare But Important Cause of Intermittent Claudication and Chronic Limb-Threatening Ischemia2020

    • Author(s)
      Azuma N, Uchida T, Kikuchi S, Sadahiro M, Shintani T, Yanagi K, Higashita R, Yamashita A, Makita Y, Kaname T.
    • Journal Title

      Circulation Journal

      Volume: 84 Issue: 7 Pages: 1183-1188

    • DOI

      10.1253/circj.CJ-20-0153

    • NAID

      130007864270

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2020-06-25
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A cDNA analysis disclosed the discordance of genotype-phenotype correlation in a patient with attenuated MPS II and a 76-base deletion in the gene for iduronate-2-sulfatase2020

    • Author(s)
      Fukuhara Y, Miura A, Yamazaki N, So T, Kosuga M, Yanagi K, Kaname T, Yamagata T, Sakuraba H, Okuyama T
    • Journal Title

      Mol Genet Metab Rep

      Volume: 25 Pages: 100692-100692

    • DOI

      10.1016/j.ymgmr.2020.100692

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Severe gastrointestinal symptoms caused by a novel DDX3X variant2020

    • Author(s)
      Okano S, Miyamoto A, Makita Y, Taketazu G, Kimura K, Fukuda I, Tanaka H, Yanagi K, Kaname T
    • Journal Title

      Eur J Med Genet

      Volume: 63 Issue: 12 Pages: 104058-104058

    • DOI

      10.1016/j.ejmg.2020.104058

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A novel homozygous missense SLC25A20 mutation in three CACT-deficient patients: clinical and autopsy data.2020

    • Author(s)
      Chinen Y, Yanagi K, Nakamura S, Nakayama N, Kamiya M, Nakayashiro M, Kaname T, Naritomi K, Nakanishi K.
    • Journal Title

      Hum Genome Var

      Volume: - Issue: 1 Pages: 11-11

    • DOI

      10.1038/s41439-020-0098-y

    • NAID

      120006892751

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy.2020

    • Author(s)
      Tanaka R, Takahashi S, Kuroda M, Takeguchi R, Suzuki N, Makita Y, Narumi-Kishimoto Y, Kaname T.
    • Journal Title

      Epileptic Disord

      Volume: 22 Issue: 4 Pages: 501-505

    • DOI

      10.1684/epd.2020.1187

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A commentary on germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.2020

    • Author(s)
      Kaname T.
    • Journal Title

      J Hum Genet

      Volume: 65 Issue: 7 Pages: 589-590

    • DOI

      10.1038/s10038-020-0767-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants2020

    • Author(s)
      Tomoko Uehara, Kota Abe, Masayuki Oginuma, Shizuka Ishitani, Hiroshi Yoshihashi, Nobuhiko Okamoto, Toshiki Takenouchi, Kenjiro Kosaki, Tohru Ishitani
    • Journal Title

      Scientific reports

      Volume: 10 Issue: 1 Pages: 1-7

    • DOI

      10.1038/s41598-020-74642-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Whole genome sequencing resolved a whole exome negative patient with congenital ichthyosis and severe atopic dermatitis2022

    • Author(s)
      Kumiko Yanagi, Miori Sato, Tomomi Hidai, Makiko Omata, Kazuhito Satou, Masahiko Yamamori, Arisa Igarashi, Taiga Aoki, Takaya Iida, Masato Kantake, Yosuke Baba, Kazuki Miyabayashi, Ichiro Nomura, Ryo Tanaka, Kazue Yoshida, Yukihiro Ohya, Yoichi Matsubara, Tadashi Kaname
    • Organizer
      日本人類遺伝学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] An aberrantly spliced FGFR2 transcript variant identified in the patient with craniosynostosis syndrome2022

    • Author(s)
      Kumiko Yanagi, Arisa Igarashi, Tomomi Hidai, Taiga Aoki, Yasuyuki Fikuhara, Tadashi Kaname
    • Organizer
      2022日本分子生物学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Two novel variants in POLA1 and BC1D8B identified in a Japanese patient with failure to thrive, mild intellectual delay, skin pigmentation and renal failure2022

    • Author(s)
      Kumiko Yanagi, Yasutsugu Chinen, Kazuhito Satou, Arisa Igarashi, Kenji Naritomi, Koichi Nakanishi, Yoichi Matsubara, Tadashi Kaname
    • Organizer
      The European Society of Human Genetics 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical features and molecular characterization of three Japanese patients with autosomal dominant Robinow syndrome caused by DVL3 variants2021

    • Author(s)
      Kumiko Yanagi, Eriko Nishi, Arisa Igarashi, Maki Omata, Yukimi Abe, Nana Kobayashi, Kazuhito Satou, Kanako Ishii, Nobuhiko Okamoto, Yoichi Matsubara, Tadashi Kaname
    • Organizer
      European Society of Human Genetics
    • Related Report
      2021 Research-status Report
  • [Presentation] Long-read whole-genome sequencing with phasing analysis reveals the cause of a suspected family with Joubert syndrome.2021

    • Author(s)
      Kumiko Yanagi, Jonathan Coker, Kaori Miyana, Makiko Omata, Tomomi Hidai, Arisa Igarashi, Kazuhito Sato, Adam Richman, Suneel Indupuru, Yoichi Matsubara, Hemant Thapar, Tadashi Kaname.
    • Organizer
      日本人類遺伝学会第66回大会
    • Related Report
      2021 Research-status Report
  • [Presentation] A Japanese girl with a novel variant of PIK3R1 showed deterioration of insulin resistance to biguanide treatment.2020

    • Author(s)
      Kumiko Yanagi, Suzuka Toguchi, Kazuhito Sato, Madoka Inoue, Kenji Naritomi, Yoichi Matsubara, Tadashi Kaname
    • Organizer
      European Society of Human Genetics
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] JIP3をコードするMAPK8IP3のrecurrent de novo variantsは痙性麻痺、指摘障害、脳梁低形成を起こす2020

    • Author(s)
      菊池敦夫、岩澤伸哉、柳久美子、小林康子、荻野谷和裕、松本浩、黒澤健司、落合正行、酒井康成、三宅紀子、新堀哲也、松本直通、要匡、青木洋子、東海林亙、呉繁夫
    • Organizer
      第27回日本遺伝子診療学会
    • Related Report
      2020 Research-status Report
  • [Presentation] A novel missense variant located within in GTP binding motif of GNAI32020

    • Author(s)
      柳 久美子、守本倫子、磯まなみ、五十嵐ありさ、松原洋一、要 匡
    • Organizer
      第43回日本分子生物学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Recognizable morphological characteristics of mandibular jaw distinguishing ARCND1 from other micrognathism Auriculocondylar2020

    • Author(s)
      柳 久美子、守本倫子、松原洋一、要 匡
    • Organizer
      日本人類遺伝学会第65回大会
    • Related Report
      2020 Research-status Report
  • [Presentation] A novel variant within the G4 box of GNAI3, one of the catalytic domains of guanine nucleotide-binding, in a Japanese patient with Auriculocondylar syndrome 12020

    • Author(s)
      Kumiko Yanagi, Noriko Morimoto, Nana Kobayashi, Yukimi Abe, Yoichi Matsubara, Tadashi Kaname
    • Organizer
      American Society of Human Genetics
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2024-01-30  

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