Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy

Anne Guimier (1) , Christopher T. Gordon (1) , François Godard (2) , Gianina Ravenscroft (3) , Myriam Oufadem (1) , Christelle Vasnier (4) , Caroline Rambaud (5, 6) , Patrick Nitschke (7) , Christine Bole-Feysot (8, 9) , Cécile Masson (7) , Stéphane Dauger (10) , Cheryl Longman (11) , Nigel G. Laing (3) , Béatrice Kugener (12, 13) , Damien Bonnet (14) , Patrice Bouvagnet (15) , Sylvie Di Filippo (16) , Vincent Probst (17) , Richard Redon (17) , Philippe Charron (18) , Agnès Rötig (1) , Stanislas Lyonnet (14, 1) , Alain Dautant (2) , Loïc De Pontual (1) , Jean-Paul Di Rago (2) , Agnès Delahodde (19) , Jeanne Amiel (1)

1 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 IBGC - Institut de biochimie et génétique cellulaires
3 Center for Medical Research, University of Western Australia and the Harry Perkins Institute for Medical Research WA 6009
4 IGM - Institut de génétique et microbiologie [Orsay]
5 SADV - Stress Abiotiques et Différenciation des Végétaux Cultivés
6 ICV - Institut Charles Viollette (ICV) - EA 7394
7 BIP-D - Plate Forme Paris Descartes de Bioinformatique
8 IRIB - Institute for Research and Innovation in Biomedicine
9 ADEN - Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau
10 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
11 West of Scotland Regional Genetics Service
12 Physiologie integrée du système d'éveil
13 Hôpital Mère-Enfant - Unité de Sommeil Pédiatrique
14 Hôpital Necker - Enfants Malades [AP-HP]
15 Laboratoire Cardiogénétique, CHU de Lyon HCL-GH Est-Hôpital Louis Pradel
16 Service de Cardiologie Pédiatrique
17 ITX - ITX - unité de recherche de l'institut du thorax
18 CHU Pitié-Salpêtrière [AP-HP]
19 FDMITO - Fonctions et dysfonctions de la mitochondrie

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.

Domaines: Sciences du Vivant [q-bio]

Anne Guimier, Christopher T. Gordon, François Godard, Gianina Ravenscroft, Myriam Oufadem, et al.. Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy. American Journal of Human Genetics, 2016, 99 (3), pp.666--673. ⟨10.1016/j.ajhg.2016.06.021⟩. ⟨hal-01831600⟩