ArticleAmerican journal of human genetics2016
Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 55 citations in OpenAlex.
- Human P53 Expression in Yeast: Investigating Its Apoptotic Effects.Mini reviews in medicinal chemistry · 2026Review
- PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.Autophagy · 2026Article
- Acute heart failure in adulthood as the first manifestation of a homozygous pyrophosphatase 2 variant, expanding the phenotypic spectrum: a case report.European heart journal. Case reports · 2025Article
- Observational
- A case of resuscitated cardiac arrest in a school-aged child with pyrophosphatase 2 deficiency.HeartRhythm case reports · 2025Article
- Conformational Dynamics of Mitochondrial Inorganic Pyrophosphatase hPPA2 and Its Changes Caused by Pathogenic Mutations.Life (Basel, Switzerland) · 2025Article
- Transcriptome Analysis of Myocardial Ischemic-Hypoxic Injury in Rats and Hypoxic H9C2 Cells.ESC heart failure · 2024Article
- Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank.eLife · 2024Article
- PPA2 Deficiency in 2 Sisters: A Rare Cause of Sudden Cardiac Death.JACC. Case reports · 2023Article
- Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene.European journal of pediatrics · 2023Article
- Identification of candidate genes responsible for chasmogamy in wheat.BMC genomics · 2023Article
- Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.Nature cardiovascular research · 2023Article
- Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.Pediatric research · 2022Article
- Latent Variables Capture Pathway-Level Points of Departure in High-Throughput Toxicogenomic Data.Chemical research in toxicology · 2022Article
- De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular CaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Yeast as a Tool to Understand the Significance of Human Disease-Associated Gene Variants.Genes · 2021Review
- The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases.Genes · 2021Review
- Clinical and biochemical footprints of inherited metabolic diseases. IV. Metabolic cardiovascular disease.Molecular genetics and metabolism · 2021Review
- Downregulation of PPA2 expression correlates with poor prognosis of kidney renal clear cell carcinoma.PeerJ · 2021Article
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Authors and funding
27 authors at 11 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sudden unexpected death in infancy occurs in apparently healthy infants and remains largely unexplained despite thorough investigation. The vast majority of cases are sporadic. Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family. PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell. We show that deletion of the orthologous gene in yeast (ppa2Δ) compromises cell viability due to the loss of mitochondria. Expression of wild-type human PPA2, but not PPA2 containing the mutations identified in affected individuals, preserves mitochondrial function in ppa2Δ yeast. Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria from the mutant yeast cells. Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants.
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