Asian T2 deficiency and HSD10 disease gene mutation identification and genotype-phenotype analysis
Project/Area Number |
15K01693
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Applied health science
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Research Institution | Chubu 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)
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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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)
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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.
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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。
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Report
(5 results)
Research Products
(44 results)
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[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
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Journal Title
Journal of Inherited Metabolic Disease
Volume: 40
Issue: 6
Pages: 845-852
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
JIMD reports
Volume: 印刷中
Pages: 59-65
DOI
ISBN
9783662558324, 9783662558331
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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
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Journal Title
Journal of Inherited Metabolic Disease
Volume: 40
Issue: 3
Pages: 395-401
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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.
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Journal Title
International Journal of Molecular Medicine
Volume: 35
Issue: 6
Pages: 1554-1560
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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