Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy

Area of Science:

• Genetics
• Molecular Biology
• Pediatrics

Background:

• Sudden unexpected death in infancy (SUDI) is a leading cause of infant mortality, often remaining unexplained.
• Genetic factors are implicated in a subset of SUDI cases, but specific genes remain unidentified.

Purpose of the Study:

• To identify the genetic cause of sudden and unexpected cardiac arrest in infants from three families.
• To elucidate the functional consequences of identified mutations in the PPA2 gene.

Main Methods:

• Whole-exome sequencing was performed on affected infants and their families.
• Functional studies in yeast (Saccharomyces cerevisiae) were conducted using gene deletion and expression systems.
• Mitochondrial function was assessed in yeast models.

Main Results:

• Compound heterozygous missense mutations in the PPA2 gene were identified in all affected infants.
• Deletion of the orthologous PPA2 gene in yeast resulted in compromised cell viability and mitochondrial loss.
• Mutant PPA2 proteins failed to restore mitochondrial function in yeast, indicating pathogenicity.

Conclusions:

• Biallelic mutations in PPA2, encoding mitochondrial pyrophosphatase, cause a severe mitochondrial disease.
• This condition leads to sudden cardiac arrest and death in infants, highlighting PPA2's critical role in human health.