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

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.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…In contrast, other CMT-linked mutations have been reported to cause a loss of charging activity, suggesting that haploinsufficiency of the enzyme may be a possible contributing factor (Griffin et al, 2014; McLaughlin et al, 2012). Supporting this hypothesis, recessive mutations in synthetases have been linked to neurodegenerative disease, as well as many multisystem disorders involving a wider range of tissues, and many of these mutations have been found to reduce aminoacylation activity in vitro (Kodera et al, 2015; McLaughlin et al, 2010; van Meel et al, 2013; Meyer-Schuman and Antonellis, 2017; Nakayama et al, 2017; Puffenberger et al, 2012; Simons et al, 2015; Taft et al, 2013; Wolf et al, 2014; Zhang et al, 2014a). Impaired synthetase function may reduce the amount of charged tRNA available for translation elongation, with a possible increase in the levels of uncharged tRNA.…”

The expanding spectrum of movement disorders in genetic epilepsies

“…76,77 Finally, patients with SLC1A2 mutations, affecting the glutamate transporter EAAT2, manifest DEE occasionally in tandem with movement disorders such as upper limb dyskinesia. 86,87 Additionally, patients with mutations in WWOX, a gene with a role in apoptosis and tumour suppression, 88 present with treatment-resistant DEE. Patients also often have pronounced dystonia and athetosis.…”

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails

“…Specifically, subjects are compound heterozygous for one missense mutation and one null allele, compound heterozygous for two missense mutations, or homozygous for a single missense mutation. 2 Consistent with this notion, functional studies have revealed that recessive disease-associated ARS mutations cause reduced protein abundance in immunoblot assays, [5][6][7][8][9][10][11][12][13][14][15][16][17] decreased mutant enzyme activity via in vitro kinetic assays, 9,[18][19][20][21][22][23][24][25] and/or diminished ability of the mutated gene to support cellular growth in yeast complementation assays. 12,13,21,22,[26][27][28][29][30][31][32][33] As such, impaired protein translation as a consequence of decreased tRNA charging is the most likely molecular mechanism for ARS-mediated recessive disease.…”