Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability

Abstract

Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA concentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions.

Biallelic mutations in mitochondrial tryptophanyl‐tRNA synthetase cause Levodopa‐responsive infantile‐onset Parkinsonism

“…However, its location in the mitochondrial localization signal of the protein gives it functional relevance. In a recent report by Musante et al, the p.Trp13Gly variant was found to significantly reduce the level of WARS2 protein in the mitochondrial fraction, indicating that this mutation leads to mislocalization . The p.Ser228Trp variant is not present in the ExAC database.…”

“…Mutations in mtARS genes have been shown to cause a multitude of phenotypes, predominantly affecting the nervous system, which can vary significantly depending on the specific mutations in a given mtARS. Recently, mitochondrial tryptophanyl‐tRNA synthetase, encoded by WARS2 , has been associated with the phenotypes of intellectual disability, leukoencephalopathy and seizures . Here, we describe a patient with pathogenic WARS2 mutations presenting with infantile‐onset, Levodopa‐responsive Parkinsonism.…”

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

“…Hence, genes linked to OXPHOS disorders include those vital for expression and stability of the long polycistronic mtDNA transcripts, which require post-transcriptional processing and modification to produce stable functional mtmRNAs, mt-rRNAs and mt-tRNAs (29,31). Likewise, mitochondria require 19 aminoacyl tRNA synthetases to attach cognate amino acids to the appropriate tRNA, with mutations in all 19 now identified (19,(34)(35)(36). Mitochondrial ribosomes consist of 80 nuclear encoded subunits, with mutations identified in only 8 so far (31,37).…”

The role of tRNA synthetases in neurological and neuromuscular disorders

“…Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS , DARS , HARS , IARS MARS , RARS , S ARS , W ARS , ARS , QARS , GARS , KARS , AARS 2 , CARS 2 , DARS 2 , EARS 2 , FARS 2 , HARS 2 , IARS 2 , LARS 2 , MARS 2 , NARS 2 , PARS 2 , RARS 2 , S ARS 2 , TARS 2 , VARS 2 , WARS 2 , YARS 2 .…”