title: Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect.
abstract: Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Cas
authors: C
authors: Simons
authors: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Laurie B
authors: LB
authors: Griffin
authors: Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
authors: Guy
authors: G
authors: Helman
authors: Undiagnosed Diseases Program, NIH, National Human Genome Research Institute, Bethesda, MD 20894, USA.
authors: Gretchen
authors: G
authors: Golas
authors: Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
authors: Amy
authors: A
authors: Pizzino
authors: Department of Hospitalist Medicine, Children's National Health System, Washington, DC 20010, USA.
authors: Miriam
authors: M
authors: Bloom
authors: Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
authors: Jennifer L P
authors: JL
authors: Murphy
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Joanna
authors: J
authors: Crawford
authors: Department of Physical Medicine and Rehabilitation, Children's National Health System, Washington, DC 20010, USA.
authors: Sarah H
authors: SH
authors: Evans
authors: Invitae, San Francisco, CA 94107, USA.
authors: Scott
authors: S
authors: Topper
authors: Department of Neuroradiology, Children's National Health System, Washington, DC 20010, USA.
authors: Matthew T
authors: MT
authors: Whitehead
authors: Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
authors: John M
authors: JM
authors: Schreiber
authors: Department of Genetics, Children's National Health System, Washington, DC 20010, USA; Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
authors: Kimberly A
authors: KA
authors: Chapman
authors: Undiagnosed Diseases Program, NIH, National Human Genome Research Institute, Bethesda, MD 20894, USA.
authors: Cyndi
authors: C
authors: Tifft
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Katrina B
authors: KB
authors: Lu
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Howard
authors: H
authors: Gamper
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Megumi
authors: M
authors: Shigematsu
authors: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Illumina, Inc., San Diego, CA 92122, USA; Departments of Integrated Systems Biology and of Pediatrics, George Washington University, Washington, DC 20052, USA.
authors: Ryan J
authors: RJ
authors: Taft
authors: Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Anthony
authors: A
authors: Antonellis
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Ya-Ming
authors: YM
authors: Hou
authors: Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA; Departments of Integrated Systems Biology and of Pediatrics, George Washington University, Washington, DC 20052, USA. Electronic address: avanderv@childrensnational.org.
authors: Adeline
authors: A
authors: Vanderver
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000412:Alanine-tRNA Ligase / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014481:United States
chemical_list: D000412:Alanine-tRNA Ligase