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Am J Hum Genet DOI:10.1016/j.ajhg.2014.03.003

Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures.

Publication TypeJournal Article
Year of Publication2014
AuthorsZhang, X, Ling, J, Barcia, G, Jing, L, Wu, J, Barry, BJ, Mochida, GH, R Hill, S, Weimer, JM, Stein, Q, Poduri, A, Partlow, JN, Ville, D, Dulac, O, Yu, TW, Lam, A-TN, Servattalab, S, Rodriguez, J, Boddaert, N, Munnich, A, Colleaux, L, Zon, LI, Söll, D, Walsh, CA, Nabbout, R
JournalAm J Hum Genet
Volume94
Issue4
Pages547-58
Date Published2014 Apr 03
ISSN1537-6605
KeywordsAmino Acyl-tRNA Synthetases, Aminoacylation, Animals, Brain Diseases, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Pedigree, Seizures, Zebrafish
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0002-9297(14)00105-0
DOI10.1016/j.ajhg.2014.03.003
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24656866?dopt=Abstract

Alternate JournalAm. J. Hum. Genet.
PubMed ID24656866
PubMed Central IDPMC3980424
Grant ListK23 NS069784 / NS / NINDS NIH HHS / United States
R01 NS035129 / NS / NINDS NIH HHS / United States
R01 NS35129 / NS / NINDS NIH HHS / United States