A novel tRNASer(AGY) 12244G > a variant impairs mitochondrial function and presents with classical MELAS phenotype

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial disorders are complex diseases affecting oxidative phosphorylation (OXPHOS).
• MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is a common subtype often caused by mitochondrial tRNA gene variants.
• The precise mechanisms of many MELAS-associated variants are not fully understood.

Purpose of the Study:

• To investigate the pathogenicity of a rare m.12244G>A variant in the MT-TS2 gene.
• To elucidate the molecular mechanisms underlying the variant's effect on mitochondrial function.
• To expand the understanding of genotype-phenotype correlations in MELAS.

Main Methods:

• Comprehensive clinical evaluation, genetic testing, and muscle tissue analysis (histopathology, biochemical assays) of a patient.
• Functional assessments of mitochondrial translation and OXPHOS.
• Systematic literature review of MT-TS2 variants and associated phenotypes.

Main Results:

• Identified the m.12244G>A variant in the tRNASer(AGY) gene, linked to a classical MELAS phenotype.
• Demonstrated impaired mitochondrial translation and OXPHOS dysfunction due to the variant.
• Observed COX-negative fibers, ragged red fibers, and reduced mitochondrial protein levels; literature review revealed diverse phenotypes for MT-TS2 variants.

Conclusions:

• Provided experimental validation for the pathogenicity of the m.12244G>A variant.
• Confirmed the variant's detrimental impact on mitochondrial function.
• Expanded the known genetic causes of MELAS and emphasized the need for functional studies of mtDNA variants.