期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 98, 期 2, 页码 347-357出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2015.12.008
关键词
-
资金
- US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) [U54HG006542]
- Regeneron Pharmaceuticals
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.
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