title: 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.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA; Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Jiqiang
authors.initials: J
authors.lastname: Ling
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, Université Paris Descartes, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, NeuroSpin, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, 91191 Gif-sur-Yvette, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.affiliation: Howard Hughes Medical Institute; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, MA 02115, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Weimer
authors.affiliation: Departments of Pediatrics and Ob/Gyn, Sanford School of Medicine, Sioux Falls, SD 57105, USA.
authors.forename: Quinn
authors.initials: Q
authors.lastname: Stein
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.affiliation: Department of Pediatric Neurology, Centre Hospitalier Universitaire de Lyon, 69007 Lyon, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, Université Paris Descartes, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, NeuroSpin, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, 91191 Gif-sur-Yvette, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Tim W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Anh-Thu N
authors.initials: AT
authors.lastname: Lam
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Sarah
authors.initials: S
authors.lastname: Servattalab
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U781, Department of Pediatric Radiology, Hôpital Necker-Enfants Malades, Imagine institute, Université Paris Descartes, 75006 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U781, Department of Genetics, Hôpital Necker-Enfants Malades, Imagine institute, Université Paris Descartes, 75006 Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U781, Department of Genetics, Hôpital Necker-Enfants Malades, Imagine institute, Université Paris Descartes, 75006 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.affiliation: Howard Hughes Medical Institute; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Söll
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute; Department of Pediatrics, Harvard Medical School, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, Université Paris Descartes, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale U1129, NeuroSpin, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, 91191 Gif-sur-Yvette, France. Electronic address: rima.nabbout@nck.aphp.fr.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D049148:Aminoacylation; D000818:Animals; D001927:Brain Diseases / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D012640:Seizures / Q000235:genetics*; D015027:Zebrafish
chemical_list: D000604:Amino Acyl-tRNA Synthetases; C020659:glutaminyl-tRNA synthetase