当前位置: X-MOL 学术Mitochondrion › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia
Mitochondrion ( IF 4.4 ) Pub Date : 2020-11-01 , DOI: 10.1016/j.mito.2020.09.003
Olatz Ugarteburu 1 , Maria Teresa Garcia-Silva 2 , Luis Aldamiz-Echevarria 3 , Laura Gort 1 , Judit Garcia-Villoria 1 , Frederic Tort 1 , Antonia Ribes 1
Affiliation  

Pathogenic mutations inNDUFAF4 have been reported in very few cases.Here we presentnew data to further delineate the phenotypic spectrum of NDUFAF4deficiency. We describe two siblingspresenting with facial dysmorphia and lactic acidosis in the neonatal period. Later on, they developed fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Abnormality of the cerebral white matter was demonstrated in one case, and cardiomyopathy in the other. Urine organic acid profile showed an increased excretion of lactate, Krebs cycle metabolites and 3-methylglutaconate. Whole-exome sequencing identified a novel homozygous nonsense mutation inNDUFAF4(c.478G>T; p.Glu160Ter), encoding a mitochondrial complex I assembly factor. The disruptive effect of the mutation was corroborated by the absence of NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I-containing supercomplexes and an abnormal accumulation of SCIII2IV1supercomplexes. Morphologically,fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. Cellular respiratory capacity in fibroblasts was also markedly reduced. In sum,weprovide insights into the physiopathological mechanisms underlying NDUFAF4 deficiency and expand the knowledge about the clinical and biochemical spectrum of this disorder.

中文翻译:

由于 NDUFAF4 突变导致的复合体 I 缺陷导致严重的线粒体功能障碍,并与早逝和畸形有关

NDUFAF4 中的致病突变在极少数情况下被报道。这里我们提供新数据以进一步描绘 NDUFAF4 缺陷的表型谱。我们描述了两个在新生儿期出现面部畸形和乳酸性酸中毒的兄弟姐妹。后来,他们患上了致命的早期脑病,伴有呼吸暂停、易怒、中枢通气不足、肝脏受累和高氨血症。一例表现为脑白质异常,另一例表现为心肌病。尿液有机酸谱显示乳酸、三羧酸循环代谢物和 3-甲基戊二酸的排泄增加。全外显子组测序在 NDUFAF4(c.478G>T;p.Glu160Ter)中发现了一个新的纯合无义突变,编码线粒体复合物 I 组装因子。患者成纤维细胞中不存在 NDUFAF4 表达,证实了突变的破坏作用。OXPHOS 组装研究表明,完全组装的复合物 I 和含有复合物 I 的超级复合物几乎检测不到水平,以及 SCIII2IV1 超级复合物的异常积累。在形态上,成纤维细胞显示出更圆的线粒体和线粒体网络分支程度降低。成纤维细胞的细胞呼吸能力也显着降低。总之,我们提供了对 NDUFAF4 缺乏症的病理生理机制的见解,并扩展了对该疾病的临床和生化谱的认识。OXPHOS 组装研究表明,完全组装的复合物 I 和含有复合物 I 的超级复合物几乎检测不到水平,以及 SCIII2IV1 超级复合物的异常积累。在形态上,成纤维细胞显示出更圆的线粒体和线粒体网络分支程度降低。成纤维细胞的细胞呼吸能力也显着降低。总之,我们提供了对 NDUFAF4 缺乏症的病理生理机制的见解,并扩展了对该疾病的临床和生化谱的认识。OXPHOS 组装研究表明,完全组装的复合物 I 和含有复合物 I 的超级复合物几乎检测不到水平,以及 SCIII2IV1 超级复合物的异常积累。在形态上,成纤维细胞显示出更圆的线粒体和线粒体网络分支程度降低。成纤维细胞的细胞呼吸能力也显着降低。总之,我们提供了对 NDUFAF4 缺乏症的病理生理机制的见解,并扩展了对该疾病的临床和生化谱的认识。
更新日期:2020-11-01
down
wechat
bug