Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.
Hum Mutat
; 38(10): 1348-1354, 2017 10.
Article
em En
| MEDLINE
| ID: mdl-28493438
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.
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Base de dados:
MEDLINE
Assunto principal:
Espasmos Infantis
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Paraplegia Espástica Hereditária
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Alanina-tRNA Ligase
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Síndrome de Lennox-Gastaut
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Microcefalia
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article