2. Academic Validation
  3. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect

Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect

  • Am J Hum Genet. 2015 Apr 2;96(4):675-81. doi: 10.1016/j.ajhg.2015.02.012.
Cas Simons 1,  Laurie B Griffin 2,  Guy Helman 3,  Gretchen Golas 4,  Amy Pizzino 3,  Miriam Bloom 5,  Jennifer L P Murphy 3,  Joanna Crawford 1,  Sarah H Evans 6,  Scott Topper 7,  Matthew T Whitehead 8,  John M Schreiber 3,  Kimberly A Chapman 9,  Cyndi Tifft 4,  Katrina B Lu 10,  Howard Gamper 10,  Megumi Shigematsu 10,  Ryan J Taft 11,  Anthony Antonellis 12,  Ya-Ming Hou 10,  Adeline Vanderver 13
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 2 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.
  • 3 Department of Neurology, Children's National Health System, Washington, DC 20010, USA.
  • 4 Undiagnosed Diseases Program, NIH, National Human Genome Research Institute, Bethesda, MD 20894, USA.
  • 5 Department of Hospitalist Medicine, Children's National Health System, Washington, DC 20010, USA.
  • 6 Department of Physical Medicine and Rehabilitation, Children's National Health System, Washington, DC 20010, USA.
  • 7 Invitae, San Francisco, CA 94107, USA.
  • 8 Department of Neuroradiology, Children's National Health System, Washington, DC 20010, USA.
  • 9 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.
  • 10 Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  • 11 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.
  • 12 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.
  • 13 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: [email protected].
PMID: 25817015 DOI: 10.1016/j.ajhg.2015.02.012
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.

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