The Association Between Mitochondrial tRNA^Glu Variants and Hearing Loss: A Case-Control Study

Area of Science:

• Genetics
• Mitochondrial Biology
• Audiology

Background:

• Non-syndromic hearing loss (NSHL) is a common congenital disorder.
• Mitochondrial DNA (mtDNA) mutations are implicated in various human diseases, including hearing impairment.
• Specific variants in mitochondrial transfer RNA genes, such as mt-tRNA^Glu, require further investigation for their role in NSHL.

Purpose of the Study:

• To investigate the frequency of mt-tRNA^Glu variants in pediatric patients with NSHL.
• To identify potential pathogenic mtDNA variants associated with NSHL.
• To assess the impact of identified variants on mitochondrial function.

Main Methods:

• Sanger sequencing was employed to screen for mt-tRNA^Glu variants in 180 NSHL patients and 100 controls.
• Phylogenetic conservation and haplogroup analyses were used to evaluate the pathogenicity of identified variants.
• Mitochondrial function assays (mtDNA content, ATP, ROS) were performed on patient-derived cells.

Main Results:

• Four potential pathogenic variants (m.T14709C, m.A14683G, m.A14692G, m.A14693G) were identified exclusively in NSHL patients.
• Patients with variants m.A14692G and m.G7444A exhibited significantly reduced mtDNA copy numbers and ATP production, alongside increased ROS levels.
• A family history of NSHL was noted in a child carrying the m.A14692G variant.

Conclusions:

• mt-tRNA^Glu variants are significant risk factors for pediatric non-syndromic hearing loss.
• The identified variants contribute to mitochondrial dysfunction, providing a molecular basis for NSHL.
• These findings underscore the importance of screening for mitochondrial variants in the diagnosis of NSHL.