Analysis of mutations in mitochondrial transfer RNA genes and the maternal inheritance of polycystic ovary syndrome

Tanzeela Nawaz ¹ Tahira Awan ¹ Humaira Zahoor ¹ Dr. Ghulam Abbas ¹ Shaheen Bibi ¹ Aziz Ud-Din ¹ Ghulam Abbas ¹ Sajid Ul Ghafoor ¹ Abdur Rehman ² Xing-Guo Li ^2* Sadia Tabassum ^1*

• ¹ Department of Zoology, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
• ² China Medical University (Taiwan), Taichung, Taiwan

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite the escalatingglobal prevalence, there is currently no definitive predisposition test available for this condition. Among the genetic causes,variations in the mitochondrial DNA (mtDNA) are increasingly recognized as a crucial contributor to the development of PCOS.However, cross-ethnic analysis of these mutations is lacking. To fill in this gap, our objective is to identify new maternal geneticrisk factors associated with PCOS by investigating the mitochondrial transfer RNA (mt-tRNA) genes in PCOS patients from Pakistanand to compare these mutations to those in patients from other ethnic groups. In a cohort of 64 Pakistani patients with PCOS, ouranalysis unveiled eight variants in five mt-tRNA genes including MT-TH, MT-TL2, MT-TS1, MT-TS2, and MT-TT genes. All of thesevariants have not been previously reported in PCOS except one we have recently identified in a Pakistani patient with PCOS.Interestingly, most of these mt-tRNA genes carry variants found in patients with PCOS across distinct ethnic groups. Furthermore,these mutations occurred in highly conserved nucleotides of tRNA, essential for ensuring the stability and biochemical functionalityof mt-tRNA. Finally, the pathogenic potential of these variations was assessed by in silico analysis. The pathogenicity prediction ofthese variants suggests their potential impact on mitochondrial dysfunction that was responsible for the clinical phenotypes ofPCOS. Our study identified novel variations in mt-tRNA genes in Pakistani women with PCOS. To our knowledge, this is the firstreport comparing mutations of mt-tRNA genes in PCOS patients across different ethnic groups. Our data revealed common mt-tRNAgenes carrying PCOS-associated mutations that may be specific to certain ethnic populations. Together, our work provides newinsights into the role of mt-tRNA genes in mitochondrial dysfunction underlying the pathophysiology of PCOS, highlighting mt-tRNAmutations as potential factors for future predisposition tests and more effective therapies for this globally prevalent condition.