Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Methylmalonic aciduria (MMA) cblB type arises from mutations in the MMAB gene, crucial for cobalamin adenosyltransferase (ATR) function.
• Understanding genotype-phenotype correlations is vital for managing this rare metabolic disorder.

Purpose of the Study:

• To investigate the functional impact of novel and known MMAB gene mutations in MMA cblB type.
• To explore the resulting cellular and mitochondrial dysfunction in patient-derived cells.

Main Methods:

• Genetic analysis of two sibling pairs with MMA cblB type, identifying novel (p.His183Leu/p.Arg190dup) and known mutations (p.Ile96Thr/p.Ser174fs).
• Expression analysis of ATR enzyme stability and half-life.
• Assessment of reactive oxygen species (ROS), mitochondrial respiration, and morphology in patient fibroblasts.

Main Results:

• Novel mutations p.His183Leu and p.Arg190dup destabilize ATR, reducing its stability and half-life.
• Patient fibroblasts exhibit increased ROS, decreased mitochondrial respiration, and altered mitochondrial structure.
• These findings indicate significant mitochondrial dysfunction in cblB patients.

Conclusions:

• MMAB gene mutations in MMA cblB type lead to destabilized ATR and profound mitochondrial dysfunction.
• Mitochondrial dysfunction is characterized by increased oxidative stress and impaired energy production.
• Restoring mitochondrial function presents a potential therapeutic target for improving clinical outcomes in MMA cblB type.