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

5 years ago

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

Jennifer N. Partlow, R. Sean Hill, Tojo Nakayama, Ganeshwaran H. Mochida, Jiqiang Ling, Malak El-Quessny, Jiang Wu, Mary R. Andriola, A. James Barkovich, Dylan J. Vaughan, Jody Weiss, Brenda J. Barry, Patricia Galvin-Parton

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. Mutations in alanyl-tRNA synthetase (AARS) are implicated in neurological disorders, but there have been limited data on the pathogenesis. We identified loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity. A lymphoblastoid cell line derived from an affected indivual showed a strong reduction in AARS protein abundance. Functional analysis of the mutations broadened the spectrum of potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23250