1. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy
- Author
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Jiang Wu, A. James Barkovich, Jiqiang Ling, Tojo Nakayama, Mary R. Andriola, R. Sean Hill, Ganeshwaran H. Mochida, Malak El-Quessny, Brenda J. Barry, Jody Weiss, Dylan J. Vaughan, Patricia Galvin-Parton, and Jennifer N. Partlow
- Subjects
0301 basic medicine ,Microcephaly ,Aminoacylation ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Article ,03 medical and health sciences ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Exome Sequencing ,Genetics ,medicine ,Protein biosynthesis ,Humans ,Amino Acid Sequence ,Genetics (clinical) ,Exome sequencing ,Mutation ,Progressive microcephaly ,Lennox Gastaut Syndrome ,Spastic Paraplegia, Hereditary ,Siblings ,Alanine-tRNA Ligase ,Infant ,Electroencephalography ,medicine.disease ,Molecular biology ,030104 developmental biology ,Child, Preschool ,Protein Biosynthesis ,Transfer RNA ,Female ,Spasms, Infantile ,030217 neurology & neurosurgery - 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 (CMT) 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. This article is protected by copyright. All rights reserved
- Published
- 2017
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