A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Neurogenetics

Background:

• Mutations in the mitochondrial DNA polymerase (POLG) gene are linked to various mitochondrial disorders.
• These mutations often disrupt mitochondrial DNA (mtDNA) integrity and maintenance, leading to depletion or deletions.
• Clinical presentations range from Alpers syndrome to chronic progressive external ophthalmoplegia.

Observation:

• A patient presented with a severe, early-onset multi-systemic mitochondrial disease, including sensorineural hearing loss, cataract, myopathy, and liver failure.
• This patient harbored a dominant p.Y955H mutation in the POLG gene.
• The p.Y955H mutation was compared to the known p.Y955C mutation using Drosophila melanogaster models and in vitro biochemistry.

Findings:

• Both p.Y955H and p.Y955C POLG mutations impair mtDNA replication.
• Both mutations exhibit a dominant-negative effect on polymerase function.
• The p.Y955H mutation demonstrates more severe polymerase dysfunction compared to p.Y955C.

Implications:

• This study elucidates the molecular consequences of a novel POLG mutation (p.Y955H).
• It highlights the correlation between specific POLG mutations and disease severity.
• Findings contribute to understanding POLG-related mitochondrial diseases and may inform future therapeutic strategies.