目的:许多细胞蛋白的功能取决于辅因子,然而,它们只与少数孟德尔疾病有牵连。这里,我们描述了细胞溶质铁硫蛋白组装系统的前两种遗传性疾病方法:通过基因组测序进行遗传检测,以确定3例小头畸形患者的潜在疾病原因,先天性脑畸形,进行性发育和神经损伤,反复感染,和致命的结果。在患者来源的皮肤成纤维细胞和斑马鱼模型中进行研究以研究生化和细胞后果。结果:代谢分析显示体液中尿嘧啶和胸腺嘧啶水平升高,但DPYD中没有致病性变异。基因组测序确定了两名患者在CIAO1中的错义变体的化合物杂合性和在第三名患者的MMS19中的框内3核苷酸缺失的纯合性。蛋白质组的深刻改变,在患者来源的成纤维细胞中观察到代谢组和脂质组.我们在斑马鱼模型中证实了CIAO1和MMS19缺陷的有害作用。结论:胞浆和核铁硫蛋白成熟的一般失败导致多效性作用。胞质铁-硫蛋白组装机制用于抗病毒宿主防御的关键功能可能很好地解释了我们患者反复发生的严重感染。
The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.
Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences.
Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models.
A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.