徳島大学 教育・研究者情報データベース(EDB)

1. 徳島大学.疾患酵素学研究センター(2007年4月1日〜2016年3月31日/->組織[徳島大学.先端酵素学研究所.次世代酵素学研究領域])

1. Yao Dengbing

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2. (英) Mizuguchi Hiroshi / (日) 水口 寛 / (読) みずぐち ひろし

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3. (英) Yamaguchi Miyoko / (日) 山口 美代子 / (読) やまぐち みよこ

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4. 山田 博司

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5. 千田 淳司([徳島大学.先端酵素学研究所.基幹研究部門])

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6. (英) Shikata Koji

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7. 木戸 博([徳島大学.先端酵素学研究所.重点研究部門])

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(英) Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.

(英) Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homo-/heterozygous variants of carnitine palmitoyltransferase II (CPT II, gene symbol CPT2). We characterized the enzymatic properties of five single and three compound CPT II variants in patients with IAE. The kinetic characteristics of WT and variant CPT IIs, expressed in COS-7 cells, indicated that the variants exert a dominant-negative effect on the homotetrameric protein of the enzyme. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the WT. Like other disease-causing mutant proteins, these variant proteins were poly-ubiquitinated and rapidly degraded by a lactacystin-sensitive proteasome pathway. COS-7 cells transfected with the compound variants had their fatty acid beta-oxidation decreased to 30-59% and intracellular ATP levels to 48-79%, and a marked reduction of mitochondrial membrane potential at 41 degrees C, compared with control cells transfected with WT at 37 degrees C. The unstable CPT II variants with decreased enzymatic activities may bring mitochondrial fuel utilization below the phenotypic threshold during high fever, and thus may play an important etiopathological role in the development of brain edema of IAE.

1. ミトコンドリア(mitochondria)
2. カルニチンパルミトイルトランスフェラーゼ 2(carnitine palmitoyltransferase 2)
3. インフルエンザ脳症(influenza-associated encephalopathy)

1. (英) Article.Affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.

2. (英) Article.PublicationTypeList.PublicationType: Journal Article

3. (英) Article.PublicationTypeList.PublicationType: Research Support, Non-U.S. Gov't