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Deficient activity of alanyl‐tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy
Author(s) -
Nakayama Tojo,
Wu Jiang,
GalvinParton Patricia,
Weiss Jody,
Andriola Mary R.,
Hill R. Sean,
Vaughan Dylan J.,
ElQuessny Malak,
Barry Brenda J.,
Partlow Jennifer N.,
Barkovich A. James,
Ling Jiqiang,
Mochida Ganeshwaran H.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23250
Subject(s) - aminoacylation , biology , microcephaly , aminoacyl trna synthetase , transfer rna , missense mutation , mutation , exome sequencing , genetics , exome , gene , rna
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.