[P1-195] Identification of TFB2M c.790C>T (His264Tyr) homozygous variant in Korean patients with intellectual disability by whole-exome sequencing
Intellectual disability (ID) is characterized by significant limitations in cognitive functioning and skills, including communication, social skills, and self-care skills. So far, over 200 genes have been identified as related to isolated ID and ID-associated disorders. In the present study, we found the TFB2M c.790C>T (His264Tyr) variation in two Korean sibling patients with ID via next generation sequencer-based whole-exome sequencing. To prove the causality between the TFB2M c.790C>T variation and mitochondrial hyperactivity, the effects of overexpression of TFB2M wild-type and variants on mitochondrial activities were investigated in the primary-cultured fibroblasts. The patients were revealed to have the TFB2M c.790C>T homozygous variation and their father had one variation, indicating autosomal-recessive inheritance in this family. The TFB2M gene encodes the TFB2M protein, which plays a role in mitochondrial DNA replication and transcription initiation. Mitochondrial gene expression in the fibroblasts showed that mRNA expression levels of mitochondrial genes in the patients were significantly higher than in the father. Mitochondrial vitality tests revealed that ATP production, ROS production, mitochondrial membrane potential, oxygen consumption rate, mitochondrial morphology, and movement were significantly higher in the patients than in the father. Furthermore, fibroblast cells overexpressing the TFB2M c.790C>T variant showed significantly higher in all of the tested mitochondrial activity compared to fibroblast cells overexpressing wild-type TFB2M. Our results suggest that the TFB2M c.790C>T variation may result in abnormal, hyperactivated mitochondrial function. [This work was supported by the grants funded by the Korea government (HI14C2296 and 2015008728) and Ajou Research Institute for Innovative Medicine.]