TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism
TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism
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DOI：
10.1002/jimd.12149
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发表时间：
2019-09-01
影响因子：
4.2
通讯作者：
Darin, Niklas
中科院分区：
文献类型：
--
作者：
Jennions, Elizabeth;Hedberg-Oldfors, Carola;Darin, Niklas
外显子组测序最近发现了基因TANGO2(运输和高尔基组织2)的突变是与反复发生的涉及横纹肌溶解、心律失常和代谢紊乱的危象相关的发育延迟的原因。这种疾病目前还不清楚，部分原因是TANGO2蛋白的细胞功能和亚细胞定位尚不清楚。此外，临床综合征及其症状、体征和实验室结果的异质性仍在定义中。在这里，我们描述了11例新的与TANGO2相关的疾病，证实并进一步扩展了先前描述的临床表型。患者是之前描述的外显子缺失或新的移码、剪接点和错义突变的纯合子或复合杂合子。所有患者都表现出发育迟缓，伴有共济失调、构音障碍、智能障碍或痉挛双瘫的迹象。重要的是，我们确定了两名受试者(年龄分别为12岁和17岁)，他们从未经历过该病典型的分解代谢诱导的代谢危机的任何明显发作。线粒体复合体II活性在与危象相关的患者中轻度降低，但在其他患者中正常。在一名死亡患者中，尸检发现大脑白质中存在异位神经元，这表明TANGO2可能在神经元迁移中发挥作用。此外，我们已经解决了几种不同的TANGO2亚型的亚细胞定位，这些亚型都不是线粒体，而是似乎主要有细胞质的定位。先前描述的高尔基体形态异常在培养的皮肤成纤维细胞中没有观察到。
Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2-related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism-induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post-mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.