Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy

Am J Hum Genet. 2016 Sep 1;99(3):666-673. doi: 10.1016/j.ajhg.2016.06.021.

Anne Guimier ¹, Christopher T Gordon ¹, François Godard ², Gianina Ravenscroft ³, Myriam Oufadem ¹, Christelle Vasnier ⁴, Caroline Rambaud ⁵, Patrick Nitschke ¹, Christine Bole-Feysot ¹, Cécile Masson ¹, Stéphane Dauger ⁶, Cheryl Longman ⁷, Nigel G Laing ³, Béatrice Kugener ⁸, Damien Bonnet ⁹, Patrice Bouvagnet ¹⁰, Sylvie Di Filippo ¹¹, Vincent Probst ¹², Richard Redon ¹², Philippe Charron ¹³, Agnès Rötig ¹, Stanislas Lyonnet ¹⁴, Alain Dautant ², Loïc de Pontual ¹, Jean-Paul di Rago ², Agnès Delahodde ¹⁵, Jeanne Amiel ¹⁶

Affiliations

1 INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France.
2 University Bordeaux, CNRS, Institute of Cellular Biochemistry and Genetics (IBGC, UMR 5095), 33000 Bordeaux, France.
3 Center for Medical Research, University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, WA 6009, Australia.
4 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
5 Forensics and Pathology Department, Raymond Poincaré University Hospital, APHP, 92380 Garches, France.
6 Pediatric Intensive Care Unit, Robert Debré University Hospital, AP-HP, and Denis Diderot Paris 7 University, Sorbonne Paris Cité, 75019 Paris, France.
7 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.
8 SIDS Reference Center of Lyon, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 69677 Bron Cedex, France.
9 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.
10 Laboratoire Cardiogénétique, Hospices Civils de Lyon, 69667 Bron, France; INSERM U1217, CNRS UMR5310, Université Lyon 1, Lyon, France.
11 Service de cardiologie pédiatrique, 59 bd Pinel, Hospices Civils de Lyon, 69667 Bron, France.
12 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.
13 Centre de référence des maladies cardiaques héréditaires, Hôpital Ambroise Paré & Hôpital Pitié-Salpêtrière, Université Versailles Saint Quentin & AP-HP, 75651 Paris Cedex 13, France.
14 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.
15 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France. Electronic address: [email protected].
16 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: [email protected].

PMID: 27523598 DOI: 10.1016/j.ajhg.2016.06.021

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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