当前位置: X-MOL 学术Clin. Genet. › 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.)
Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-01-30 , DOI: 10.1111/cge.13706
Daan M Panneman 1, 2 , Saskia B Wortmann 1, 3, 4, 5 , Charlotte A Haaxma 6 , Peter M van Hasselt 7 , Nicole I Wolf 8 , Yvonne Hendriks 9 , Benno Küsters 10 , Sjenet van Emst-de Vries 2, 11 , Els van de Westerlo 2, 11 , Werner J H Koopman 2, 11 , Liesbeth Wintjes 12 , Frans van den Brandt 12 , Maaike de Vries 1 , Dirk J Lefeber 6, 12 , Jan A M Smeitink 1 , Richard J Rodenburg 1, 12
Affiliation  

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.

中文翻译:

NGLY1的变异会导致智力残疾,肌阵挛性癫痫,感觉运动性轴索性多发性神经病和线粒体功能障碍。

NGLY1编码参与糖蛋白降解的N-聚糖酶,作为内质网相关降解途径的一部分。已经描述了该基因的变体引起以神经运动障碍,神经病,智力残疾和畸形特征为特征的多系统疾病。在这里,我们描述了NGLY1中具有致病性变异的四名患者。由于患者的临床特征和实验室结果提示多系统线粒体疾病,因此进行了肌肉活检。肌肉中的生化分析表明,所有患者的ATP生成速率均大大降低,而各个OXPHOS酶的活性则从正常到降低。使用mtDNA分析和整个外显子组测序未发现任何线粒体疾病基因的致病变异。在所有四个病人中 一名患者显示成纤维细胞的基础和最大耗氧率降低。与对照细胞系相比,线粒体形态功能成纤维细胞分析显示出患者的特异性差异。总之,NGLY1的变异会影响线粒体能量代谢,进而可能促进临床疾病进程。一名患者显示成纤维细胞的基础和最大耗氧率降低。与对照细胞系相比,线粒体形态功能成纤维细胞分析显示出患者的特异性差异。总之,NGLY1的变异会影响线粒体能量代谢,进而可能有助于临床疾病进程。
更新日期:2020-03-26
down
wechat
bug