Abstract
OBJECTIVE: In this study, we examined the genetic, medical, and molecular traits of two Han Chinese families with the tRNA(Cys) G5783A mutation to investigate the relationship between mitochondrial DNA (mtDNA) mutations and major depressive disorder (MDD). METHODS: Clinical data and comprehensive mitochondrial genomes were collected from the two families. Variants were assessed for evolutionary conservation, allelic frequencies, and their structural and functional impacts. The study involved detailed mitochondrial whole genome analysis, as well as phylogenetic and haplotype analyses of the probands and other family members. RESULTS: We detailed the genetic, clinical, and molecular profiles of two Han Chinese families with MDD. These families exhibited a range of depression severities and notably low penetrance of MDD. Analysis of the mitochondrial genomes revealed a homoplasmic tRNA(Cys) G5783A mutation. This mutation was found at a highly conserved cytosine at position 50 (C50) in the TΨC stem of tRNA(Cys), with a conserved coefficient of 100% across 17 species. Additionally, distinctive mtDNA polymorphisms associated with haplogroups H2 were identified. CONCLUSION: The identification of the tRNA(Cys) G5783A mutation in two unrelated individuals with depression strongly suggests that this mutation may play a role in the development of major depressive disorder (MDD). These Chinese families revealed low penetrances of MDD. Thus, the phenotypic tRNA(Cys) G5783A mutation expression associated with MDD may be impacted by nuclear modifier gene(s) or environmental factors.