Mutations in QARS, Encoding Glutaminyl-tRNA Synthetase, Cause Progressive Microcephaly, Cerebral-Cerebellar Atrophy, and Intractable Seizures

Abstract

Progressive microcephaly is a heterogeneous condition with causes including mutations in genes encoding regulators of neuronal survival. Here, we report the identification of mutations in QARS (encoding glutaminyl-tRNA synthetase [QARS]) as the causative variants in two unrelated families affected by progressive microcephaly, severe seizures in infancy, atrophy of the cerebral cortex and cerebellar vermis, and mild atrophy of the cerebellar hemispheres. Whole-exome sequencing of individuals from each family independently identified compound-heterozygous mutations in QARS as the only candidate causative variants. QARS was highly expressed in the developing fetal human cerebral cortex in many cell types. The four QARS mutations altered highly conserved amino acids, and the aminoacylation activity of QARS was significantly impaired in mutant cell lines. Variants p.Gly45Val and p.Tyr57His were located in the N-terminal domain required for QARS interaction with proteins in the multisynthetase complex and potentially with glutamine tRNA, and recombinant QARS proteins bearing either substitution showed an over 10-fold reduction in aminoacylation activity. Conversely, variants p.Arg403Trp and p.Arg515Trp, each occurring in a different family, were located in the catalytic core and completely disrupted QARS aminoacylation activity in vitro. Furthermore, p.Arg403Trp and p.Arg515Trp rendered QARS less soluble, and p.Arg403Trp disrupted QARS-RARS (arginyl-tRNA synthetase 1) interaction. In zebrafish, homozygous qars loss of function caused decreased brain and eye size and extensive cell death in the brain. Our results highlight the importance of QARS during brain development and that epilepsy due to impairment of QARS activity is unusually severe in comparison to other aminoacyl-tRNA synthetase disorders.

Structure of the ArgRS–GlnRS–AIMP1 complex and its implications for mammalian translation

“…Notably, Lys394 is an ubiquitylation site (19), and modification of this residue is expected to disrupt the interface between QRS and RRS as well as that between QRS and AIMP1. The binding of RRS by the C-terminal domain of QRS is consistent with previous functional studies showing that mutation of Arg403 to Trp of human QRS severely disrupted the interaction between RRS and QRS (possibly via local structural perturbation), whereas the two mutations at the N-terminal domain of QRS did not affect its binding to RRS (20).…”

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

“…Two families with autosomal recessive primary microcephaly and intractable seizures harboring compound heterozygous QARS mutations have been recently reported. 7 In this study, we present the detailed molecular and clinical analysis of a Japanese family with two siblings affected with early-onset epileptic encephalopathies (EOEEs) in which wholeexome sequencing confirmed the presence of QARS mutations.…”

Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities

“…In the April 2014 issue of the American Journal of Human Genetics, Zhang et al reported two unrelated families with loss-of-function mutations in QARS (MIM 603727) as cause of a neurodegenerative disease with progressive microcephaly, cerebral-cerebellar atrophy, hypomyelination or delayed myelination, and intractable seizures [1]. In vitro experiments confirmed significant impairment of QARS aminoacetylation in mutant cell lines, and zebrafish with homozygous loss of QARS function showed extensive cell death in the brain with decreased brain and eye size.…”

“…c Schematic representation of QARS and the position of variants; neither mutation has been reported before. Human RefSeq NP_ 005042.1 and E. coli YP_ 488960.1 sequences are used for comparison (MIM 611524) and TSEN54 (MIM 608755), and progressive cerebello-cerebral atrophy due to SEPSECS (MIM 613009) mutations [1]. All these disorders are characterized by a significant, if not prominent, posterior fossa involvement.…”