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Asian T2 deficiency and HSD10 disease gene mutation identification and genotype-phenotype analysis

Research Project

Project/Area Number 15K01693
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied health science
Research InstitutionChubu University

Principal Investigator

AOYAMA Yuka  中部大学, 臨床検査技術教育・実習センター, 講師 (40460498)

Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords先天代謝異常症 / ケトン体代謝 / β-ケトチオラーゼ / ACAT1 / スプライシング異常 / minigene splice実験 / HSD10病 / 先天性ケトン体代謝異常症 / T2欠損症 / ACAT1遺伝子 / HSD17B10遺伝子 / HSD17B10 / スプライシング / Minigene splicing 実験
Outline of Final Research Achievements

In this study, mutational analysis of an Indian T2-deficient patient revealed a homozygous c.121-13T>A mutation located at the polypyrimidine tract of the splice acceptor site of intron 2, and exon 3 skipping was identified by cDNA analysis using cycloheximide. I made the c.121-13T>A, T>C, and T>G mutant constructs followed by making a wild-type minigene construct that included an ACAT1 segment from exon 2 to 4 for a splicing experiment. The minigene splicing experiment demonstrated that exon 3 skipping was induced not only by c.121-13T>A mutation, but also by the other two substitutions. The c.121-13 position of ACAT1 gene appears to be an originally low-recognized site. In the routine diagnostic practice, in silico tools can predict the potential consequences of mutations on splicing, but their results are not so reliable. The minigene splicing experiment remains the most reliable method to unravel splicing abnormalities.

Academic Significance and Societal Importance of the Research Achievements

T2欠損症とHSD10病に関する遺伝子解析は、アジアの国々ではまだ研究が進んでいない国もあり診断が難しい状況にある。本研究では、ACAT1遺伝子のスプライスアクセプター部位のポリピリミジン領域存在するc.121-13T>Aのホモ接合性の変異がT2欠損症を引き起こすことをminigene splicing実験にて明らかにした。これら実験系の確立およびスプライシング異常を引き起こす変異の同定は、T2欠損症だけでなく他疾患においても診断の助けとなるはずである。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (44 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (8 results) Journal Article (13 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 13 results,  Open Access: 12 results,  Acknowledgement Compliant: 4 results) Presentation (23 results) (of which Int'l Joint Research: 9 results)

  • [Int'l Joint Research] Sohag University(エジプト)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Sohang University(Egypt)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] KMC, Manipal University/Rainbow Hospital for Women and Children/MILS International India(India)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Tripoli University(リビア)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] National Children’s Hospital/Vinmec International Hospital/Ministry of Science and Technology(ベトナム)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Sohang University(Egypt)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Catholic University of the Sacred Heart/Niguarda Ca’ Granda Metropolitan Hospi.(Italy)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] KMC, Manipal University(India)

    • Related Report
      2015 Research-status Report
  • [Journal Article] Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency2019

    • Author(s)
      Fukao T, Sasai H, Aoyama Y, Otsuka H, Ago Y, Matsumoto H, Abdelkreem E.
    • Journal Title

      Journal of Human Genetics

      Volume: 64 Issue: 2 Pages: 99-111

    • DOI

      10.1038/s10038-018-0524-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intronic antisense Alu elements have a negative splicing effect on the inclusion of adjacent downstream exons2018

    • Author(s)
      Nakama M, Otsuka H, Ago Y, Sasai H, Abdelkreem E, Aoyama Y, Fukao T.
    • Journal Title

      Gene

      Volume: 664 Pages: 84-89

    • DOI

      10.1016/j.gene.2018.04.064

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis2017

    • Author(s)
      Sasai H, Aoyama Y, Otsuka H, Abdelkreem E, Naiki Y, Kubota M, Sekine Y, Itoh M, Nakama M, Ohnishi H, Fujiki R, Ohara O, Fukao T
    • Journal Title

      Journal of Inherited Metabolic Disease

      Volume: 40 Issue: 6 Pages: 845-852

    • DOI

      10.1007/s10545-017-0065-z

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Japanese Male Siblings with 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency (HSD10 Disease) Without Neurological Regression2017

    • Author(s)
      Akagawa S, Fukao T, Akagawa Y, Sasai H, Kohdera U, Kino M, Shigematsu Y, Aoyama Y, Kaneko K
    • Journal Title

      JIMD reports

      Volume: 32 Pages: 81-85

    • DOI

      10.1007/8904_2016_570

    • ISBN
      9783662543849, 9783662543856
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency2017

    • Author(s)
      Abdelkreem E, Akella RR, Dave U, Sane S, Otsuka H, Sasai H, Aoyama Y, Nakama M, Ohnishi H, Mahmoud S, Abd El Aal M, Fukao T
    • Journal Title

      JIMD reports

      Volume: 印刷中 Pages: 59-65

    • DOI

      10.1007/8904_2016_26

    • ISBN
      9783662558324, 9783662558331
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Single-nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene. Molecular Genetics and Genomic Medicine2017

    • Author(s)
      Sasai H, Aoyama Y, Otsuka H, Abdelkreem E, Nakama M, Hori T, Ohnishi H, Turner L, Fukao T
    • Journal Title

      Molecular Genetics and Genomic Medicine

      Volume: 5 Issue: 2 Pages: 177-184

    • DOI

      10.1002/mgg3.275

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two Libyan siblings with beta-ketothiolase deficiency: A case report and review of literature2017

    • Author(s)
      Abdelkreem E, Alobaidy H, Aoyama Y, Mahmoud S, El Aal MA, Fukao T
    • Journal Title

      The Egyptian Journal of Medical Human Genetics

      Volume: 18 Issue: 2 Pages: 100-203

    • DOI

      10.1016/j.ejmhg.2016.11.001

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years’ experience of a medical center in northern Vietnam2017

    • Author(s)
      Nguyen KN, Abdelkreem E, Colombo R, Hasegawa Y, Can NT, Bui TP, Le HT, Tran MT, Nguyen HT, Trinh HT, Aoyama Y, Sasai H, Yamaguchi S, Fukao T, Vu DC
    • Journal Title

      Journal of Inherited Metabolic Disease

      Volume: 40 Issue: 3 Pages: 395-401

    • DOI

      10.1007/s10545-017-0026-6

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] A novel mutation (c.121-13T>A) in the polypyrimidine tract of the splice acceptor site of intron 2 causes exon 3 skipping in mitochondrial acetoacetyl-CoA thiolase gene2017

    • Author(s)
      Aoyama Y, Sasai H, Abdelkreem E, Otsuka H, Nakama M, Kumar S, Aroor S,Shukla A, Fukao T
    • Journal Title

      Molecular Medicine Reports

      Volume: 印刷中 Issue: 6 Pages: 3879-3884

    • DOI

      10.3892/mmr.2017.6434

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Beta-Ketothiolase Deficiency: Resolving Challenges in Diagnosis. Journal of Inborn Errors of Metabolism and Screening2016

    • Author(s)
      Abdelkreem E, Otsuka H, Sasai H, Aoyama Y, Hori T, Abd El Aal M, Mahmoud S, Fukao T
    • Journal Title

      Journal of Inborn Errors of Metabolism & Screening

      Volume: 4 Pages: 1-9

    • DOI

      10.1177/2326409816636644

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site2016

    • Author(s)
      Otsuka H, Sasai H, Nakama M, Aoyama Y, Abdelkreem E, Ohnishi H, Konstantopoulou V, Sass JO, Fukao T
    • Journal Title

      Molecular Medicine Reports

      Volume: 14 Issue: 5 Pages: 4906-4910

    • DOI

      10.3892/mmr.2016.5819

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 3-hydroxy-3-methylglutaryl CoA(HMGCL)lyase欠損症における新たな遺伝子診断法2016

    • Author(s)
      青山友佳
    • Journal Title

      中部大学生命健康科学研究所紀要

      Volume: 12 Pages: 87-91

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency2015

    • Author(s)
      Aoyama Y, Yamamoto T, Sakaguchi N, Ishige M, Tanaka T, Ichihara T, Ohara K, Kouzan H, Kinosada Y, Fukao T.
    • Journal Title

      International Journal of Molecular Medicine

      Volume: 35 Issue: 6 Pages: 1554-1560

    • DOI

      10.3892/ijmm.2015.2184

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ACAT1遺伝子におけるイントロン9のsplice acceptor siteのpoly T/C stretch変異はエクソン10のスキップをきたす2018

    • Author(s)
      笹井英雄、中原茉保、宮部亜里紗、仲間美奈、大塚博樹、松本英樹、吾郷耕彦 青山友佳、深尾敏幸
    • Organizer
      第109回東海臨床遺伝・代謝懇話会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Functional analysis of mutant recombinant HSD17B10 proteins using an E. Coli expression system2018

    • Author(s)
      Sasai H, Ohnishi H, Akagawa S, Akiba K, Hasegawa Y, Kobayashi M, Otsuka H, Aoyama Y, Ago Y, Fukao T.
    • Organizer
      Annual Symposium of the Society for the Study of Inborn Errors of Metabolism
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 日本におけるHMGCS欠損症患者の変異酵素の特徴2018

    • Author(s)
      吾郷耕彦、大塚博樹、Elsayed Abdelkreem、笹井英雄、仲間美奈、青山友佳、西村洋子、中島葉子、伊藤哲哉、深尾敏幸、渡邊順子、福井香織、秋山和政、李知子
    • Organizer
      第60回日本先天代謝異常学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 乳児期の3ヒドロキシ酪酸脱水素酵素(Bdh1)KOマウスにおける絶食負荷試験2018

    • Author(s)
      大塚博樹、木村豪、吾郷耕彦、仲間美奈、Elsayed Abdelkreem、青山友佳、松本英樹、笹井英雄、大西秀典、深尾敏幸
    • Organizer
      第60回日本先天代謝異常学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis2017

    • Author(s)
      Sasai H, Aoyama Y, Otsuka H, Abdelkreem E, Naiki Y, Kubota M, Sekine Y, Itoh M, Nakama M, Ohnishi H, Fujiki R, Ohara O, Fukao T
    • Organizer
      Asia-Pacific Conference on Human Genetics
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 絶食負荷試験において3 ヒドロキシ酪酸脱水素酵素 (Bdh1) KOマウスではケトン体産生が障害される2017

    • Author(s)
      大塚博樹、木村豪、吾郷耕彦、仲間美奈、Abdelkreem Elsayed, 青山友佳、笹井英雄、大西秀典、大沢匡毅、川島祐介、小原収、山口清次、深尾敏幸
    • Organizer
      第58回日本先天代謝異常学会
    • Related Report
      2017 Research-status Report
  • [Presentation] リコンビナントHSD17B10タンパクを用いたHSD10病の病態解析2017

    • Author(s)
      笹井英雄、大西秀典、赤川翔平、秋葉和壽、長谷川行洋、小林正久、大塚博樹、青山友佳、深尾敏幸
    • Organizer
      第58回日本先天代謝異常学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Pathophysiology of 3-Hydroxybutyrate Dehydrogenase (3HBD) deficiency in Ketone Body Metabolism using a Bdh1 Knockout Mouse Model2017

    • Author(s)
      Otsuka H, Kimura T, Ago Y, Sasai H, Nakama M, Aoyama Y, Abdelkreem E, Ohnishi H, Osawa M, Yamaguchi S, Kawashima Y, Ohara O, Fukao T
    • Organizer
      International Congress of Inborn Errors of Metabolism
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis2017

    • Author(s)
      Sasai H, Aoyama Y, Otsuka H, Abdelkreem E, Naiki Y, Kubota M, Sekine Y, Itoh M, Nakama M, Ohnishi H, Fujiki R, Ohara O, Fukao T
    • Organizer
      International Congress of Inborn Errors of Metabolism
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 3 ヒドロキシ酪酸脱水素酵素Bdh1 KO マウスの作成とその病態解析2016

    • Author(s)
      大塚博樹、木村 豪、仲間美奈、Elsayed Abdelkreem、青山友佳、笹井英雄、大西秀典、大沢匡毅、深尾敏幸
    • Organizer
      第58回日本先天代謝異常学会
    • Place of Presentation
      京王プラザホテル(東京都、新宿)
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Clinical and mutational characterizations of 10 Indian patients with beta-ketothiolase deficiency2016

    • Author(s)
      Elsayed Abdelkreem, Radha Rama Devi Akella, Usha Dave, Sudhir Sane, Hiroki Otsuka, Hideo Sasai, Yuka Aoyama, Mina Nakama, Hidenori Ohnishi, Shaimaa Mahmoud, Mohamed Abd El Aal, Toshiyuki Fukao
    • Organizer
      第58回日本先天代謝異常学会
    • Place of Presentation
      京王プラザホテル(東京都、新宿)
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] An c. IVS9-9 T >A substitution identified in beta-ketothiolase deficient patients results in exon 10 skipping in most transcripts of ACAT1 gene2016

    • Author(s)
      Fukao T, Sasai H, Otsuka H, Aoyama Y, Elsayed A, Nakama M, Hori T, Ohnishi H, Turner L, Sweetman L
    • Organizer
      Annual symposium of the society for the study of inborn errors of metabolism
    • Place of Presentation
      Rome, Italy
    • Year and Date
      2016-09-06
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Oral glucose tolerance tests in Japanese citrin-deficient siblings before and after MCT-oil supplementation2016

    • Author(s)
      Otsuka H, Sasai H, Nakama M, Aoyama Y, Abdelkreem E, Kawamoto N, Kawamoto M, Ohnishi H, Numakura C, Hayasaka K, Fukao T
    • Organizer
      Annual symposium of the society for the study of inborn errors of metabolism
    • Place of Presentation
      Rome, Italy
    • Year and Date
      2016-09-06
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] ACAT1 遺伝子イントロン2 のc.121-13T > A によるエクソン3スキップとスプライシングの予測2016

    • Author(s)
      青山友佳、笹井英雄、大塚博樹、Elsayed Abdelkreem、深尾敏幸
    • Organizer
      第43回日本マススクリーニング学会
    • Place of Presentation
      ホテルさっぽろ芸文館(北海道、札幌)
    • Year and Date
      2016-08-26
    • Related Report
      2016 Research-status Report
  • [Presentation] ACAT1遺伝子のイントロン2内のc.121-13T>A変異によるエクソン3のスキップ2015

    • Author(s)
      青山友佳、笹井英雄、大塚博樹、Sandeep Kumar、Anju Sukla、 Shrikiran Aroor、Suneel Mundkur、深尾敏幸
    • Organizer
      第57回日本先天代謝異常学会
    • Place of Presentation
      大阪国際会議場(大阪府)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] ACAT1遺伝子のエクソン10のc.949G>Aによるエクソン10スキップ2015

    • Author(s)
      大塚博樹、笹井英雄、青山友佳、深尾敏幸
    • Organizer
      第57回日本先天代謝異常学会
    • Place of Presentation
      大阪国際会議場(大阪府)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] ミトコンドリアHMG-CoA合成酵素欠損症の2症例における臨床的、生化学的共通点2015

    • Author(s)
      中島葉子、深尾敏幸、加藤沙耶香、中野優、笹井英雄、青山友佳、長谷川有紀、酒井好美、吉川哲史、伊藤哲哉
    • Organizer
      第57回日本先天代謝異常学会
    • Place of Presentation
      大阪国際会議場(大阪府)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] OXCT1ヘテロキャリアーでもケトアシドーシス発作を起こしうる2015

    • Author(s)
      笹井英雄、青山友佳、大塚博樹、堀友博、藤木亮次、小原收、深尾敏幸
    • Organizer
      第57回日本先天代謝異常学会
    • Place of Presentation
      大阪国際会議場(大阪府)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] シトリン欠損症の兄妹例で行ったグルコース負荷試験およびMCTオイル投与の効果2015

    • Author(s)
      大塚博樹、笹井英雄、青山友佳、川本典生、川本美奈子、松井永子、深尾敏幸
    • Organizer
      第57回日本先天代謝異常学会
    • Place of Presentation
      大阪国際会議場(大阪府)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] ACAT1遺伝子におけるイントロン9のsplice acceptor siteでのpolyT/C内の単一塩基置換(T to A)がエクソン10のスキップをきたす2015

    • Author(s)
      笹井秀雄、大塚博樹、青山友佳、堀友博、久保田一生、折居建治、深尾敏幸
    • Organizer
      第60回日本人類遺伝学会
    • Place of Presentation
      京王プラザホテル(東京都)
    • Year and Date
      2015-10-14
    • Related Report
      2015 Research-status Report
  • [Presentation] Two patients with atypical form and one with infantile form of HSD10 disease were identified in Japan2015

    • Author(s)
      Fukao T, Sasai H, Aoyama Y, Akiba K, Goto M, Hasegawa Y, Kobayashi M, Ida H, Akagawa S, Hasegawa Y, Yamaguchi S, Shigematsu Y.
    • Organizer
      Annual symposium of the society for the study of inborn erroros of metabolism
    • Place of Presentation
      Lyon (France)
    • Year and Date
      2015-09-01
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] First two patients with mitochondrial HMG-CoA synthase deficiency in Asia2015

    • Author(s)
      Nakajima Y, Fukao T, Nakano Y, Sasai H, Aoyama Y, Kato S, Hasegawa Y, Sakai Y, Yoshikawa T, Ito T.
    • Organizer
      Annual symposium of the society for the study of inborn erroros of metabolism
    • Place of Presentation
      Lyon (France)
    • Year and Date
      2015-09-01
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] OXCT1 heterozygous carriers could develop severe ketoacidotic episodes in conjunction with ketogenic stresses2015

    • Author(s)
      Sasai H, Aoyama Y, Ohtsuka H, Ohara O, Fukao T.
    • Organizer
      Annual symposium of the society for the study of inborn erroros of metabolism
    • Place of Presentation
      Lyon (France)
    • Year and Date
      2015-09-01
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research

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Published: 2015-04-16   Modified: 2022-02-16  

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