Molecular basis of inborn errors of ketone body metabolism:mainly tertiary structural changes of protein and abnormalities of splicing
| Project/Area Number |
18591148
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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, Professor (70260578)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,980,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | thiolase / CoA transferase / Inborn errors of metabolism / ketone body metabolism / splicing / transcription / nonsense-mediated RNA decay / tertiary structural model / 遺伝子変異 / 蛋白3次構造 / ACAT1 / OXCT / チオラーゼ欠損症 / CoAトランスフェラーゼ欠損症 |
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| Research Abstract |
The study for molecular basis of inborn errors of ketone body metabolism, especially focused on tertiary structural changes by missense mutations and abnormal splicing, was performed. In collaboration with Finland group, we first showed crystal structure of human mitochondrial acetoacetyl-CoA thiolase (T2) homotetramer. and showed a mechanism of pots ssiurnion activation. We identified mutations in T2 deficiency and succinyl-CoA: 3-ketoacid CoA transferase deficiency. We analyzed 7 new missense mutations by transient expression analysis of cDNA and evaluated temperature sensitive activity and stability. Then we discussed the effect of mutant on the tertiary structure. In case of SCOT deficiency, we identified and characterized a unique splicing mutation. In T2 deficiency, we also identified an exonic mutation which activates cryptic splice donor site just its 5-base upstream. We dearly showed that this exonic mutation was responsible for the aberrant splicing by mini gene splicing experiment. We also showed that alu-mediated genomic rearrangement is one of the cause of T2 deficirncy in some patients.
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Report
(3 results)
Research Products
(34 results)
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[Journal Article] Kinetic and Expression Analyses of Seven Novel Mutations in Mitochondrial Acetoacetyl-CoA Thiolase (T2) : Identification of a K_m Mutant and an Analysis of the Mutational Sites in the Structure.2007
Author(s)
Sakurai S, Fukao T, Haapalainen AM, Zhang G, Yamada S, Lilliu F, Yano S, Robinson P, Gibson MK, Wanders RJA, Mitchell GA, Wierenga RK, Kondo N
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Journal Title
Related Report
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[Journal Article] Aberrant peroxisome morphology in peroxisomal beta-oxidation enzyme deficiencies.2006
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
Brain Dev. 28
Pages: 287-292
NAID
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