Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

  • Hum Mutat. 2017 Oct;38(10):1348-1354. doi: 10.1002/humu.23250.
Tojo Nakayama  1  2  3 ,  Jiang Wu  4 ,  Patricia Galvin-Parton  5 ,  Jody Weiss  5 ,  Mary R Andriola  5 ,  R Sean Hill  1  2  6 ,  Dylan J Vaughan  1  2 ,  Malak El-Quessny  1  2 ,  Brenda J Barry  1  2  6 ,  Jennifer N Partlow  1  2  6 ,  A James Barkovich  7 ,  Jiqiang Ling  4  8 ,  Ganeshwaran H Mochida  1  2  3  9
Affiliations
  • 1. Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
  • 2. Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
  • 3. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
  • 4. Department of Microbiology and Molecular Genetics, Medical School, University of Texas Health Science Center, Houston, Texas.
  • 5. Department of Pediatrics, Stony Brook University Medical Center, Stony Brook, New York.
  • 6. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts.
  • 7. Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
  • 8. Graduate School of Biomedical Sciences, Houston, Texas.
  • 9. Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
PMID: 28493438 DOI: 10.1002/humu.23250
Abstract

Aminoacyl-transfer RNA (tRNA) synthetases ligate Amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole-exome Sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.

Keywords
AARS; aminoacylation defect; hypomyelination; microcephaly; transfer RNA.