2. Academic Validation
  3. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy

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

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.

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