ArticleAmerican journal of human genetics2014
Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84 citing papers in PubMed, 136 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Genetic architecture and prognostic significance of suspected fetal microcephaly: evidence from prenatal exome sequencing in a large prospective cohort.Human genomics · 2026Article
- Oxidative stress-driven transcriptomic remodeling in human astrocytes reveals network signatures associated with neurodegenerative and cardiovascular processes.Computational and structural biotechnology journal · 2026Article
- Proteomic Characterization of Human Peripheral Blood Mononuclear Cells Exposed to a 50 Hz Magnetic Field.International journal of molecular sciences · 2025Article
- QARS1 associated developmental epileptic encephalopathy: first report of a rare homozygous missense variant from Pakistan causing nonepileptic phenotype in a family of seven patients and a comprehensive review of the literature.Molecular biology reports · 2025Review
- Molecular biomarkers for the prognosis of breast cancer: role of amino acid metabolism genes.Journal of physiology and biochemistry · 2025Article
- Serine mistranslation induces the integrated stress response through the P stalk.The Journal of biological chemistry · 2025Article
- Exome sequencing identifies novel genes associated with cerebellar volume and microstructure.Communications biology · 2025Article
- Childhood-onset focal epilepsy and acute para-infectious encephalopathy in a patient with biallelic QARS1 variants.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects.Journal of inherited metabolic disease · 2025Review
- Article
- Aminoacyl-tRNA synthetase defects in neurological diseases.IUBMB life · 2025Review
- Third trimester diagnosis of a compound heterozygous QARS1 mutation based upon microcephaly and abnormal placenta.Case reports in perinatal medicine · 2025Article
- Simultaneous determination of cytosolic aminoacyl-tRNA synthetase activities by LC-MS/MS.Nucleic acids research · 2024Article
- Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic.Epilepsia open · 2024Article
- A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex.Neuroscience bulletin · 2024Article
- A model organism pipeline provides insight into the clinical heterogeneity of TARS1 loss-of-function variants.HGG advances · 2024Article
- Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA mNature communications · 2024Article
- Predictive modeling provides insight into the clinical heterogeneity associated withbioRxiv : the preprint server for biology · 2024Article
- Coordination between aminoacylation and editing to protect against proteotoxicity.Nucleic acids research · 2023Article
24 more citing papers are in PubMed but not listed here.
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25 authors at 8 institutions in 2 countries.
Funding
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.
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