Research Article

葡萄牙多发性酰基辅酶A脱氢酶缺乏症患者的分子及临床研究

卷 19, 期 7, 2019

页: [487 - 493] 页: 7

弟呕挨: 10.2174/1566524019666190507114748

价格: $65

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摘要

背景:多发性酰基辅酶A氢酶缺乏症(MADD)是一种先天性罕见的代谢性疾病,临床表型广泛,进化多样。这种天生的代谢错误是由ETFA、ETFB或ETFDH基因突变引起的,这些基因由线粒体ETF和ETF:QO蛋白编码。据报道,相当多的患者对核黄素口服补充剂反应积极,这构成了病理学的原型治疗。 目的:在葡萄牙患者中发现的ETFA、ETFB和ETFDH基因突变,尽可能将生化和临床结果与突变对受影响蛋白结构和稳定性的影响联系起来,以便更好地在分子水平上理解MADD的发病机制。 方法:在新生儿筛查过程中,根据血斑中有机酸和/或酰基肉碱的尿谱特征,确定MADD患者。收集所有患者的基因型、临床和生化数据。在硅结构分析中,使用生物信息学工具进行了ETF:QO分子模型识别错义突变。 结果:对8例葡萄牙MADD患者的临床及生化特征进行了调查。基因型分析鉴定出5个ETFDH突变,包括1个扩展(p.X618QextX*14), 2个剪接突变(c.34+5G>C和c .405+3A>T)和两个错义突变(ETF:QO-p.Arg155Gly和ETF: QO-p.Pro534Leu)和一个ETFB变异(ETFβ- p.Arg191Cys)。含有ETFDH突变p.X618QextX*14, c.34+5G>C 和ETF:QO-p.Arg155Gly的纯合子患者。Arg155Gly均表现为严重(致命)的MADD表型。然而,当这些突变中的任何一个与已知的ETF:QO-p.Pro534Leu杂合时轻度变异,严重的临床疗效有部分和暂时减弱。实际上,后者破坏了与ETF交互的循环的稳定性,没有造成重大的功能后果。然而,ETF:QO中位置155定位于泛醌结合和膜相互作用域,预计会干扰蛋白结构和膜插入,功能影响严重。因此,分子模型的结构分析被证明是一个有价值的工具,在临床表型严重程度的背景下,使突变的影响合理化。 结论:先进的分子诊断,结构分析和临床相关性表明,在一个等位基因中具有严重预后突变的MADD患者实际上可以通过与另一个等位基因中较轻的突变互补而恢复到较温和的表型。 然而,这些患者仍处于不稳定的代谢平衡中,在分解代谢应激或继发性病理期间可能出现严重的致命结果,因此需要严格的临床随访。

关键词: II型谷氨酸尿症,核黄素反应性-MADD,结构生物化学,罕见疾病,先天性代谢错误,线粒体疾病,新生儿筛查。

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