ClinVar

In a 9-year-old boy with mitochondrial DNA depletion syndrome-19 (MTDPS19; 618972), Punzi et al. (2018) identified compound heterozygous mutations in the SLC25A10 gene. The maternal allele carried a c.304A-T transversion (c.304A-T, NM_001270888.1), resulting in a lys102-to-ter (K102X) substitution, whereas the paternal allele carried 2 variants: a c.684C-T transition, resulting in a synonymous pro228-to-pro (P228P) substitution, and an intronic c.790-37G-A transition (606794.0002). The mutations were found by trio-based whole-exome sequencing. The K102X mutation was not found in the ExAC database. The c.684C-T transition had a frequency of 0.0014 and the splice site mutation a frequency of 0.0011 in the ExAC database. Patient fibroblasts showed a 10-fold decrease in SLC25A10 transcripts compared to controls. PCR analysis indicated that the L102X mutation likely resulted in nonsense-mediated mRNA decay, whereas both paternal mutations resulted in altered splicing. Western blot analysis did not detect the SLC25A10 protein. In vitro functional expression studies showed negligible, if any, transport activity for malate/phosphate exchange, consistent with a loss of function. In addition, patient cells showed a decrease in both the NADPH/NADP+ and GSH/GSSG ratios as well as a growth defect under stress conditions. Studies in yeast lacking the Slc25a10 ortholog showed impaired growth, impaired mitochondrial respiration, decreased mtDNA, and increased vulnerability to oxidative stress compared to controls.