Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations
Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations
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DOI：
10.1016/j.ajhg.2015.12.008
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发表时间：
2016-02-04
影响因子：
9.8
通讯作者：
Yang, Yaping
中科院分区：
文献类型：
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作者：
Lalani, Seema R.;Liu, Pengfei;Yang, Yaping
横纹肌溶解的潜在遗传病因仍然难以捉摸的个体呈现复发性代谢危机和肌肉无力的很大一部分。通过外显子组测序，我们在12名患有偶发性横纹肌溶解、低血糖、高氨血症和危及生命的心动过速易感性的受试者中发现了编码转运和高尔基组织2同源物（果蝇）的TANGO2双等位基因突变。在4个无血缘关系的西班牙裔/拉丁裔个体中发现了复发性纯合c. 460G> A （p. Gly154Arg）突变，在2个欧洲血统家庭中发现了影响外显子3-9的纯合-34 kb缺失。一名西班牙/欧洲混血的个体发现c. 460G> A （p. Gly154Arg）为复合杂合，外显子3-9缺失。此外，在一个中东阿拉伯家族中发现了一个纯合子外显子4-6缺失。在对照数据库中没有报道这些变化的纯合子。与对照相比，来自复发性c. 460G> a （p. Gly154Arg）突变受试者的成纤维细胞显示出内质网应激增加和高尔基体密度降低的证据。我们的研究结果表明，TANGO2中的c. 460G> A （p. Gly154Arg）突变和外显子3-9杂合缺失分别存在于拉丁裔/西班牙裔和欧洲人群中，导致这些人群中纯合子的相当高的发病率。
The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c. 460G> A (p. Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous -34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c. 460G> A (p. Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c. 460G> A (p. Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c. 460G> A (p. Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.