Infantile-Onset Progressive Leukoencephalopathy with Deafness
In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; 601421.0010), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism.
Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy
In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; 601421.0011) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis.