Format

Send to

Choose Destination
Hum Mutat. 2017 Oct;38(10):1348-1354. doi: 10.1002/humu.23250. Epub 2017 Jun 23.

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

Author information

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.

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

PMID:
28493438
PMCID:
PMC5599341
DOI:
10.1002/humu.23250
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center