2005 Fiscal Year Final Research Report Summary
Molecular basis of inborn errors of ketone body metabolism : mainly basic studies for responsible genes
| Project/Area Number |
16591019
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Gifu University |
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Principal Investigator |
FUKAO Toshiyuki Gifu University, Graduate School of Medicine Department of Pediatrics, Associate professor, 大学院・医学系研究科, 助教授 (70260578)
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| Project Period (FY) |
2004 – 2005
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| Keywords | thiolase / CoA transferase / inborn errors of metabolism / ketone body metabolism / methylation / Alu sequence / "Mild" mutation / tertiary structure |
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| Research Abstract |
1.Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency
1)We revealed and proved that SCOT deficient patients with "mild" mutations did not always show permanent ketosis which is pathognomonic feature of SCOT deficiency.
2)In a SCOT deficient patient, we found exons 6 and 7 skipping, which was caused by G>A substitution at the end nucleotide of exon 6. We analyzed heteronuclear RNA and cytosolic RNA and revealed that mRNA with single exon 6 skipping was degraded rapidly by nonsense-mediated RNA decay. Since mRNA with exon 6 and 7 skipping was in frame and although it was minor transcript in nuclear RNA, this mRNA became a major product in cytosolic fraction.
2.Mitochondrial acetyoacetyl-CoA thiolase (T2) deficiency
1)A coupled assay with tiglyl-CoA had been widely used for the enzymatic diagnosis of T2 deficiency in Europe and USA. We revealed and proved that the result of coupled assay using tiglyl-CoA was normal in two T2 deficient patients with "mild" mutations. This means that T2 deficient patients with "mild" mutations had been mis-diagnosed as normal using the coupled assay with tiglyl-CoA.
2)We identified a large T2 gene deletion including exons 2-4 caused by unequal homologous recombination. This is the first mutation caused by this mechanism in T2 gene.
3.Liver specific suppression of human SCOT gene expression.
We analyzed status of methylation in CpG islands around SCOT gene promotor regions in HeLa cells and hepatoblastoma cell lines and murine hepatic tissues and cardiac muscle. Unexpectedly, the CpG islands around SCOT promotor regions were hypomethylated in even hepatoblastoma cell lines and murine hepatic tissues where SCOT gene was almost completely suppressed.
4.Tertiary structure of human thiolase family.
We determined a crystal tertiary structure of cytosolic acetoacetyl-CoA thiolase and found several new findings in enzyme mechamism using the structure.
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Research Products
(38 results)
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[Journal Article] Leaky phenotype of X-linked agammaglobulinaemia in a Japanese family.2005
Author(s)
Kaneko H, Kawamoto N, Asano T, Mabuchi Y, Horikoshi H, Teramoto T, Matsui E, Kondo M, Fukao T, Kasahara K, Kondo N.
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Journal Title
Clin Exp Immunol. 140
Pages: 520-523
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II.2005
Author(s)
Kato T, Kato Z, Kuratsubo I, Tanaka N, Ishigami T, Kajihara J, Sukegawa-Hayasaka K, Orii K, Isogai K, Fukao T, Shimozawa N, Orii T, Kondo N, Suzuki Y.
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Journal Title
J Hum Genet 50
Pages: 395-402
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases.2005
Author(s)
Yoshikawa K, Matsui E, Kaneko H, Fukao T, Inoue R, Teramoto T, Shinoda S, Fukutomi O, Aoki M, Kasahara K, Kondo N.
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Journal Title
Int J Mol Med. 16
Pages: 827-831
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype.2004
Author(s)
Fukao T, Chen P, Ren J, Kaneko H, Zhang GX, Kondo M, Yamamoto K, Furuichi Y, Takeda S, Kondo N, Lavin MF
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Journal Title
Oncogene 23
Pages: 1498-1506
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of somatic and germ-line mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case.2004
Author(s)
Nagao-Watanabe M, Fukao T, Matsui E, Kaneko H, Inoue R, Kawamoto N, Kasahara K, Nagai M, Ichiki Y, Kitajima Y, Kondo N
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Journal Title
Clin Genet 66
Pages: 236-238
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Relatively common mutations of the Bloom syndrome gene in the Japanese population.2004
Author(s)
Kaneko H, Isogai K, Fukao T, Matsui E, Kasahara K, Yachie A, Seki H, Koizumi S, Arai M, Utunomiya J, Miki Y, Kondo N
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Journal Title
Int J Mol Med 14
Pages: 439-442
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Aberrant peroxisome morphology in peroxisomal beta-oxidation enzyme deficiencies.
Author(s)
Funato M, Shimozawa N, Nagase T, Takemoto Y, Suzuki Y, Imamura Y, Matsumoto T, Tsukamoto T, Kojidani T, Osumi T, Fukao T, Kondo N.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
