CIAO1和MMS19缺乏:一种致命的神经退行性现象型,由细胞质Fe-S集群蛋白组装障碍引起
Clara D M van Karnebeek1, Maja Tarailo-Graovac2, René Leen3
1Amsterdam UMC location University of Amsterdam, Departments of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands; Departments of Medical Genetics and Pediatrics, Centre for Molecular Medicine and Therapeutics, Faculty of Pharmaceutical Science, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; United for Metabolic Diseases, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
我们发现了两种新的遗传性疾病,影响细胞体铁硫蛋白组装系统. 这些遗传缺陷导致严重的发育问题和患者的复发性感染.
科学领域:
- 生物化学 生物化学
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 细胞蛋白质功能依赖于辅因子,但它们在孟德尔病中的作用往往被低估.
- 影响辅因子系统的遗传性疾病很少见,这凸显了我们对遗传疾病的理解上的差距.
研究的目的:
- 研究两种新型遗传性疾病的遗传基础,这些疾病影响细胞质铁硫蛋白组装系统.
- 描述这些新发现的遗传缺陷的生化和细胞后果.
主要方法:
- 基因组测序是在三名患有小头症,脑部形,神经障碍和复发性感染的患者身上进行的.
- 利用患者衍生的皮肤纤维细胞和斑马鱼模型来研究已识别的遗传变异的功能影响.
- 在患者纤维细胞上进行了蛋白质组,代谢组和脂质组分析.
主要成果:
- 在受影响的患者中,基因分析揭示了CIAO1中的复合异性变体和MMS19中的同性缺失.
- 观察到 uracil 和 thymine 水平升高,但排除了 DPYD 中的致病变体.
- 在CIAO1和MMS19的缺陷导致了细胞蛋白质组,代谢组和脂质组的深刻改变,在斑马鱼模型中得到证实.
结论:
- 细胞和核铁硫蛋白质成熟的系统性失败是观察到的类效应的基础.
- 细胞质铁硫蛋白组装机械对于抗病毒宿主防御至关重要,解释了患者的严重感染.
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