In a 24-year-old man with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with seizures (NEMMLAS; 617710), Theisen et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion, resulting in a lys313-to-met (K313M) substitution at a conserved residue, and a 3-bp in-frame deletion (c.298_300delCTT; 604733.0004), resulting in the deletion of leu100 at a conserved residue in the catalytic core domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The K313M variant was found at a low frequency in the ExAC database (18 of 121,412 alleles, 0.0001483) and the gnomAD database (74 of 282,690 alleles, 2.62 x 10(-4)). However, it was not found in homozygous state. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%).
In 2 boys, born of unrelated Dutch parents (family F2), with NEMMLAS, Wortmann et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion in exon 6, resulting in a lys313-to-met (K313M) substitution at a highly conserved residue in the anti-codon recognition domain, and a 1-bp deletion in exon 6 (c.797delC; 604733.0005), resulting in a frameshift and premature termination (Pro266ArgfsTer10). An unrelated patient (I6), born of unrelated Canadian parents (family F5), without seizures was compound heterozygous for K313M and a c.134G-T transversion in exon 2, resulting in a gly45-to-val (G45V; 604733.0006) substitution at a conserved residue within a small loop that covers the tRNA binding site. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. They were filtered against the dbSNP (build 137) and gnomAD databases. In the gnomAD database, the K313M and c.797delC variants were found at low frequencies (0.0001407 and 4.07 x 10(-5), respectively), and the G45V variant was not listed. Studies of patient cells showed that the K313M mutant protein was sensitive to proteolytic degradation.
In 2 sisters, born of unrelated Swedish parents, with NEMMLAS, Maffezzini et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: K313M and a c.833T-G transversion, resulting in a val278-to-gly (V278G; 604733.0010) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast showed variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function.
In a 22-year-old Swedish woman with NEMMLAS, Ilinca et al. (2022) identified compound heterozygosity for the K313M and V278G mutations in the WARS2 gene. She had onset of persistent epilepsy in the neonatal period and Levodopa-responsive parkinsonism. Functional studies of the variant and studies of patient cells were not performed.
