【摘 要】
：
目的：多种酰基辅酶A脱氢酶缺乏症(MADD)是一种中国人常见的脂肪酸氧化代谢紊乱.本研究分析了42例MADD患者的临床特点、基因突变谱及其突变的病理功能.方法：分析了MADD患者
【机 构】
：
上海交通大学医学院附属新华医院 上海儿科医学研究所内分泌、遗传代谢病研究室
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目的：多种酰基辅酶A脱氢酶缺乏症(MADD)是一种中国人常见的脂肪酸氧化代谢紊乱.本研究分析了42例MADD患者的临床特点、基因突变谱及其突变的病理功能.方法：分析了MADD患者的临床及实验室特点和ETFDH基因.取4例MADD患者皮肤进行原代培养,Western Blot及细胞免疫荧光研究患者皮肤成纤维细胞ETFDH蛋白表达量及稳定性的变化,根据in vitro probe assay方法,培养基中添加棕榈酸,96小时后分析培养上清中酰基肉碱谱.通过构建突变质粒转染293T细胞的模型探讨ETFDH基因1 3种错义突变对ETF.QO蛋白酶活性及稳定性的影响.结果：儿童起病患者除肌无力症状外可伴有低血糖、脑发育不良、肝大等症状,而成人均只表现为肌病；所有患者均有短、中、长链酰基肉碱的增高,儿童患者C12、C14、C14：1较成人组显著升高.42例患者ETFDH基因突变检出率为95.2％,未发现携带ETFA/B基因突变的患者.共发现ETFDH基因44种突变,其中错义突变占多数.A84T突变为本组患者热点突变(23.5％).Western Blot及细胞免疫荧光显示4例患者皮肤成纤维细胞的ETFDH蛋白表达量较正常人减少；皮肤成纤维细胞培养上清中短、中、长链酰基肉碱较正常对照显著升高；随着培养基中核黄素浓度升高上清中酰基肉碱水平有所下降.13种错义突变均可使ETF.QO蛋白酶活性降低；FAD区及泛醌结合区的错义突变可使ETF.QO蛋白表达量显著下降,前导肽区突变对蛋白表达量无明显影响.结论：儿童MADD患者临床表现较成人患者重,ETFDH基因A84T为本组患者最常见突变.ETFDH基因突变可导致ETF.QO蛋白量减少,核黄素可改善患者皮肤成纤维细胞中ETFDH蛋白功能.ETFDH错义突变可使ETF,QO蛋白酶活性降低及稳定性下降,但前导肽区突变对蛋白稳定性无明显影响.
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