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

Abstract

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.

The molecular aetiology of tRNA synthetase depletion: induction of aGCN4amino acid starvation response despite homeostatic maintenance of charged tRNA levels

“…6). We thus confirmed that the reduced growth rate caused by doxycycline-shut-off of Gln4p is indeed associated with reduced cellular ribosome content, as well as a reduction in expression of 21 The average protein production rate still decreases as a function of the Gln4p abundance ( Fig. 5D; red dashed line), in good agreement with the measurements (Fig.…”

“…Semi-dominant mutations in cytosolic tRNA synthetases (GARS, YARS, AARS, MARS and KARS) have also been shown to result in various forms of Charcot-Marie-Tooth neuronal disorders (17) (18) (19) (20). Mutations in the human glutamine tRNA synthetase, QARS, can cause brain developmental disorders such as microcephaly (21) (22). The mechanisms behind these various conditions are still unclear, though in vitro biochemical assays, together with yeast complementation assays of several mutant tRNA synthetases, have indicated loss of aminoacylation activity (19) (23).…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…In contrast, other CMT-linked mutations have been reported to cause a loss of charging activity, suggesting that haploinsufficiency of the enzyme may be a possible contributing factor (Griffin et al, 2014; McLaughlin et al, 2012). Supporting this hypothesis, recessive mutations in synthetases have been linked to neurodegenerative disease, as well as many multisystem disorders involving a wider range of tissues, and many of these mutations have been found to reduce aminoacylation activity in vitro (Kodera et al, 2015; McLaughlin et al, 2010; van Meel et al, 2013; Meyer-Schuman and Antonellis, 2017; Nakayama et al, 2017; Puffenberger et al, 2012; Simons et al, 2015; Taft et al, 2013; Wolf et al, 2014; Zhang et al, 2014a). Impaired synthetase function may reduce the amount of charged tRNA available for translation elongation, with a possible increase in the levels of uncharged tRNA.…”

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

“…Recently, a growing number of mutations in cytoplasmic ARSs genes, including QARS (MIM# 603727) (Zhang et al., ), DARS (MIM# 603084) (Novarino et al., ; Taft et al., ), MARS (MIM# 156560) (Novarino et al., ), KARS (MIM# 601421) (McMillan et al., ), AARS (MIM# 601065) (Simons et al., ), and RARS (MIM# 107820) (Wolf et al., ), have been identified in recessive disorders affecting the central nervous system. The shared phenotypes among these recessive conditions, including progressive microcephaly (McMillan et al., ; Zhang et al., ), hypomyelinating leukodystrophy (Taft et al., ; Wolf et al., ), and epileptic encephalopathy (Kodera et al., ), suggest a possible commonality in the ARSs‐related molecular pathology underlying these neurodegenerative disorders.…”