热不稳定化合物的变种肉碱palmitoyltransferase二世和受损的线粒体燃料利用率与流感相关的脑病。
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姚明D, Mizuguchi H,山口M,山田H,城户Chida J, K Shikata说,H
热不稳定化合物的变种肉碱palmitoyltransferase二世和受损的线粒体燃料利用率与流感相关的脑病。
哼Mutat。2008; 29(5): 718 - 27所示。doi: 10.1002 / humu.20717。
- PubMed ID
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18306170 (在PubMed]
- 文摘
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与流感相关的脑病(IAE)的特征是持续高烧、发热性惊厥、严重脑水肿和高死亡率否则看似健康的人。我们有报道称,大部分患者禁用或致命,管理学院与暂时性升高血清acylcarnitine高烧期间,表现出一种不耐热的表现型复合homo - /杂合变异体的肉碱palmitoyltransferase II (CPT II基因符号CPT2)。我们描述了五个单和酶学性质的三个化合物CPT II变体接到患者。WT的动力学特征和变异CPT IIs, COS-7表达细胞,表明,变异产生显性负影响homotetrameric蛋白质的酶。在变异中,三个复合变化中发现严重的脑病患者;[c。1055 t > G (p.Phe352Cys);c。1102 g > A (p.Val368Ile)]、[c。1511 c > 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.