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J Hum Genet. 2015 Feb;60(2):97-101. doi: 10.1038/jhg.2014.103. Epub 2014 Dec 4.

Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy.

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Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
Division of Radiology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
Department of Molecular Biology, Yokohama City University School of Medicine and Graduate School of Medical Science, Yokohama, Japan.


Aminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.

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