Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy
Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy
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DOI：
10.1016/j.ajhg.2015.12.009
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发表时间：
2016-02-04
影响因子：
9.8
通讯作者：
Haack, Tobias B.
中科院分区：
文献类型：
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作者：
Kremer, Laura S.;Distelmaier, Felix;Haack, Tobias B.
由于极端的临床和遗传异质性，线粒体疾病的分子诊断具有挑战性。通过外显子组测序，我们在三个不相关的个体中发现了 TANGO2 的三种不同的双等位基因截短突变，这些个体患有婴儿期发作的偶发性代谢危机，其特征是脑病、低血糖、横纹肌溶解、心律失常，以及提示线粒体脂肪酸氧化缺陷的实验室检查结果。在疾病过程中，所有个体均出现全脑萎缩，并伴有认知障碍和锥体征。 TANGO2（运输和高尔基组织 2）编码一种蛋白质，该蛋白质具有将高尔基膜重新分配到果蝇内质网中的推定功能，并且已在小鼠中证实其线粒体定位。对突变成纤维细胞中棕榈酸依赖性呼吸的研究表明，线粒体 b-氧化存在功能缺陷。我们的结果表明 TANGO2 缺陷是临床上可识别的多器官受累儿科疾病的原因。
Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial b-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multiorgan involvement.