In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene: a paternally inherited 598C-G transversion in exon 6 resulting in a leu200-to-val (L200V) substitution at a highly conserved residue, and a maternally inherited 1102G-T transversion in exon 10 resulting in a val368-to-leu (V368L; 600783.0002) substitution at a highly conserved residue. The mutations were found by linkage analysis followed by candidate gene sequencing. Neither mutation was found in 1,942 control individuals. Study of patient lymphoblasts showed that the 598C-G mutation also created an alternative splice site, resulting in an in-frame deletion of 12 codons in exon 6 (delta200-211). The deletion transcript was present at much lower levels in the unaffected father compared to the affected children. Both mutant missense proteins were expressed, could dimerize, and localized to the mitochondria in mammalian cells, but the deletion transcript was poorly expressed, suggesting that it is unstable. Both missense mutations had significantly decreased enzymatic activity compared to wildtype, with the V368L mutation showing a more severe effect. Modeling of the homologous mutations in yeast also indicated that the V368L mutant had a more severe effect on enzyme activity. Based on the functions of mitochondrial tRNA synthetases and cellular defects resulting from their mutation, Pierce et al. (2011) speculated that mutations in HARS2 result in decreased mitochondrial translation and respiratory chain defects in affected tissues.
