A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Mitochondrial diseases are often caused by genetic mutations.
• Interpreting novel genetic variants in mitochondrial disease diagnosis can be challenging.
• Complex V deficiency is a severe form of mitochondrial disease.

Purpose of the Study:

• Identify the genetic cause of severe neonatal encephalopathy in two siblings.
• Validate the pathogenicity of identified variants using functional studies.
• Investigate the molecular mechanism of complex V deficiency.

Main Methods:

• Whole exome sequencing
• Enzymatic testing and oxygen consumption rate measurement in fibroblasts
• Immunoblotting and 3D modeling for protein interaction analysis

Main Results:

• A heterozygous ATP5A1 mutation was identified in the siblings, causing complex V deficiency.
• Patients showed reduced ATP5A1 expression and impaired complex V assembly.
• Functional complementation restored complex V activity, confirming pathogenicity.

Conclusions:

• Whole exome sequencing combined with functional studies is crucial for diagnosing mitochondrial diseases.
• The identified ATP5A1 mutation disrupts complex V subunit interaction and stability.
• This study highlights the importance of functional validation in genetic variant interpretation.