title: Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy.
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.
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Anne
authors: A
authors: Guimier
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Christopher T
authors: CT
authors: Gordon
authors: University Bordeaux, CNRS, Institute of Cellular Biochemistry and Genetics (IBGC, UMR 5095), 33000 Bordeaux, France.
authors: François
authors: F
authors: Godard
authors: Center for Medical Research, University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, WA 6009, Australia.
authors: Gianina
authors: G
authors: Ravenscroft
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Myriam
authors: M
authors: Oufadem
authors: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
authors: Christelle
authors: C
authors: Vasnier
authors: Forensics and Pathology Department, Raymond Poincaré University Hospital, APHP, 92380 Garches, France.
authors: Caroline
authors: C
authors: Rambaud
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Patrick
authors: P
authors: Nitschke
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Christine
authors: C
authors: Bole-Feysot
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Cécile
authors: C
authors: Masson
authors: Pediatric Intensive Care Unit, Robert Debré University Hospital, AP-HP, and Denis Diderot Paris 7 University, Sorbonne Paris Cité, 75019 Paris, France.
authors: Stéphane
authors: S
authors: Dauger
authors: West of Scotland Regional Genetics Service, Southern General Hospital, Glasgow and South East Scotland Regional Genetics Service, Department of Clinical Genetics, Western General Hospital, Edinburgh EH4 2XU, UK.
authors: Cheryl
authors: C
authors: Longman
authors: Center for Medical Research, University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, WA 6009, Australia.
authors: Nigel G
authors: NG
authors: Laing
authors: SIDS Reference Center of Lyon, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 69677 Bron Cedex, France.
authors: Béatrice
authors: B
authors: Kugener
authors: Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de Référence Malformations Cardiaques Congénitales Complexes (M3C), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
authors: Damien
authors: D
authors: Bonnet
authors: Laboratoire Cardiogénétique, Hospices Civils de Lyon, 69667 Bron, France; INSERM U1217, CNRS UMR5310, Université Lyon 1, Lyon, France.
authors: Patrice
authors: P
authors: Bouvagnet
authors: Service de cardiologie pédiatrique, 59 bd Pinel, Hospices Civils de Lyon, 69667 Bron, France.
authors: Sylvie
authors: S
authors: Di Filippo
authors: Inserm UMR 1087 / CNRS UMR 6291, l'institut du thorax, Université de Nantes, 44007 Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, l'institut du thorax, Service de Cardiologie, 44093 Nantes, France.
authors: Vincent
authors: V
authors: Probst
authors: Inserm UMR 1087 / CNRS UMR 6291, l'institut du thorax, Université de Nantes, 44007 Nantes, France; Centre Hospitalier Universitaire (CHU) Nantes, l'institut du thorax, Service de Cardiologie, 44093 Nantes, France.
authors: Richard
authors: R
authors: Redon
authors: Centre de référence des maladies cardiaques héréditaires, Hôpital Ambroise Paré & Hôpital Pitié-Salpêtrière, Université Versailles Saint Quentin & AP-HP, 75651 Paris Cedex 13, France.
authors: Philippe
authors: P
authors: Charron
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Agnès
authors: A
authors: Rötig
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
authors: Stanislas
authors: S
authors: Lyonnet
authors: University Bordeaux, CNRS, Institute of Cellular Biochemistry and Genetics (IBGC, UMR 5095), 33000 Bordeaux, France.
authors: Alain
authors: A
authors: Dautant
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
authors: Loïc
authors: L
authors: de Pontual
authors: University Bordeaux, CNRS, Institute of Cellular Biochemistry and Genetics (IBGC, UMR 5095), 33000 Bordeaux, France.
authors: Jean-Paul
authors: JP
authors: di Rago
authors: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France. Electronic address: agnes.delahodde@i2bc.paris-saclay.fr.
authors: Agnès
authors: A
authors: Delahodde
authors: INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France. Electronic address: jeanne.amiel@inserm.fr.
authors: Jeanne
authors: J
authors: Amiel
mesh_terms: D000483:Alleles; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000473:pathology; D011756:Diphosphates; D059472:Exome / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020043:Genes, Essential / Q000235:genetics; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D007223:Infant; D043564:Inorganic Pyrophosphatase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D050296:Microbial Viability; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D017494:Proton Pumps / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011756:Diphosphates; D024101:Mitochondrial Proteins; D017494:Proton Pumps; D029701:Saccharomyces cerevisiae Proteins; C107241:diphosphoric acid; D043564:Inorganic Pyrophosphatase; C470576:PPA2 protein, S cerevisiae; C509848:PPA2 protein, human