2000 Fiscal Year Annual Research Report

先天性ケトン体代謝異常症の分子病態-サクシニル-CoA:3-ケト酸CoAトランスフェラーゼ欠損症を中心として-

Research Project

Project/Area Number	11670754
Research Institution	Gifu University
Principal Investigator	深尾敏幸岐阜大学, 医学部・附属病院, 助手 (70260578)
Co-Investigator(Kenkyū-buntansha)	伊上良輔岐阜大学, 医学部・附属病院, 助手 (60273132) 祐川和子岐阜大学, 医学部, 助手 (60115409)
Keywords	β-ケトチオラーゼ欠損症 / ミトコンドリア・アセトアセチル-CoAチオラーゼ / サクシニル-CoA:3-ケト酸CoAトランスフェラーゼ / 遺伝子クローニング / 遺伝子変異 / 発現調節 / ケトン体
Research Abstract	ヒトSCOT遺伝子をクローニングし,本遺伝子が約150kb以上の大きさで,17のエクソンをもつこと,そのすべてのエクソン/イントロン境界を明らかにした.また英国,オランダ,米国の3症例の遺伝子変異を同定し,もっとも表現型の軽い英国の症例では遺伝子変異が残存活性をもつ変異であることを明らかにした.またSCOT遺伝子がなぜ正常肝細胞で発現しないのかをあきらかにするためSCOT上流域の解析を行った.約3kbの配列を決定し,基本的なプロモーターにはSp1が結合して活性化されることを明らかにし,肝臓特異的な抑制に関与すると思われる領域を検討した。 T2欠損症ではスペイン5症例の蛋白遺伝子解析を行った。1例はDelE85とG152Aの複合ヘテロ接合体,1例はG152AとE345Vの複合ヘテロ接合体,1例はK124Rのホモ接合体,1例はQ145Eのホモ接合体,最後の1例は380C>Tのホモ接合体であった.380C>Tはエクソン5上にあり,この変異によってエクソン内にスプライスアクセプター部位が生じ,ほとんどがこの部位でスプライシングが生じていた.またミスセンス変異のうちQ145E変異のみが残存活性を有する変異であることを明らかにした.また遺伝子変異を決定した26例について主治医にアンケート調査を行い,臨床経過,予後,遺伝子型と臨床型の関連について調べた。この報告はT2欠損症ではじめて行われた臨床追跡調査であり,意義深い。T2欠損症は診断さえつけば,以後の重篤な発作は軽度の蛋白制限などにより防がれており,予後もこれまで報告されていた以上によいことがわかった。また臨床的重症度は遺伝子型と明らかな相関はなかった。

Research Products
(8 results)

All Other

All Publications (8 results)

[Publications] Fukao T: "Succinyl-CoA : 3-ketoacid CoA transferase (SCOT) : Cloning of human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations."Genomics. 68. 144-151 (2000)
[Publications] Watanabe H: "Molecular basis of very-long-chain acyl-CoA dehydrogenase deficiency in 3 Israeli patients : identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping."Human Mutation. 15. 430-438 (2000)
[Publications] Doi T: "Milder childhood form of very long-chain acyl-CoA dehydrogenase deficiency in a 6-year-old Japanese boy."European Journal of Pediatrics. 159. 908-911 (2000)
[Publications] Fukao T: "Myopathic form of very-long chain acyl-CoA dehydrogenase deficiency : Evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl."Pediatric Research. (in press).
[Publications] Fukao T: "The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (Beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients."Molecular Genetics and Metabolism. (in press).
[Publications] Gibson KM: "Molecular and enzymatic methods for detection of genetic defects in the distal pathways of branched-chain amino acid metabolism. in Branched chain amino acids, part B"Methods in Enzymology. 324. 432-453 (2000)
[Publications] Nakamura K: "A novel single base substitution (380C>T) that activates a 5 bases-downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondcrial acetoacetyl-CoA thiolase gene."Molecular Genetics and Metabolism. (in press).
[Publications] Mitchell GA: "Chapter 102 Inborn errors of ketone body catabolism.In Metabolic and Molecular Bases of Inherited Disease (8th edition)"McGraw-Hill. 30 (2001)

2000 Fiscal Year Annual Research Report

先天性ケトン体代謝異常症の分子病態-サクシニル-CoA:3-ケト酸CoAトランスフェラーゼ欠損症を中心として-

Principal Investigator

深尾 敏幸 岐阜大学, 医学部・附属病院, 助手 (70260578)

Research Products

[Publications] Fukao T: "Succinyl-CoA : 3-ketoacid CoA transferase (SCOT) : Cloning of human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations."Genomics. 68. 144-151 (2000)

[Publications] Watanabe H: "Molecular basis of very-long-chain acyl-CoA dehydrogenase deficiency in 3 Israeli patients : identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping."Human Mutation. 15. 430-438 (2000)

[Publications] Doi T: "Milder childhood form of very long-chain acyl-CoA dehydrogenase deficiency in a 6-year-old Japanese boy."European Journal of Pediatrics. 159. 908-911 (2000)

[Publications] Fukao T: "Myopathic form of very-long chain acyl-CoA dehydrogenase deficiency : Evidence for temperature-sensitive mild mutations in both mutant alleles in a Japanese girl."Pediatric Research. (in press).

[Publications] Fukao T: "The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (Beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients."Molecular Genetics and Metabolism. (in press).

[Publications] Gibson KM: "Molecular and enzymatic methods for detection of genetic defects in the distal pathways of branched-chain amino acid metabolism. in Branched chain amino acids, part B"Methods in Enzymology. 324. 432-453 (2000)

[Publications] Nakamura K: "A novel single base substitution (380C>T) that activates a 5 bases-downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondcrial acetoacetyl-CoA thiolase gene."Molecular Genetics and Metabolism. (in press).

[Publications] Mitchell GA: "Chapter 102 Inborn errors of ketone body catabolism.In Metabolic and Molecular Bases of Inherited Disease (8th edition)"McGraw-Hill. 30 (2001)

深尾敏幸岐阜大学, 医学部・附属病院, 助手 (70260578)