title: Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.
abstract: We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand; Department of Pathology, University of Otago, Christchurch 8140, New Zealand.
authors: Hannah
authors: H
authors: Kennedy
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Tobias B
authors: TB
authors: Haack
authors: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors: Verity
authors: V
authors: Hartill
authors: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
authors: Lavinija
authors: L
authors: Mataković
authors: Metabolic Unit, University Children's Hospital Basel (UKBB), 4056 Basel, Switzerland.
authors: E Regula
authors: ER
authors: Baumgartner
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Howard
authors: H
authors: Potter
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Richard
authors: R
authors: Mackay
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Charlotte L
authors: CL
authors: Alston
authors: Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast BT12 6BA, UK.
authors: Siobhan
authors: S
authors: O'Sullivan
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Robert
authors: R
authors: McFarland
authors: Department of Clinical Biochemistry, Royal Victoria Hospital, Belfast BT12 6BA, UK.
authors: Grainne
authors: G
authors: Connolly
authors: Department of Pathology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
authors: Caroline
authors: C
authors: Gannon
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Richard
authors: R
authors: King
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Scott
authors: S
authors: Mead
authors: Department of Cardiology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Ian
authors: I
authors: Crozier
authors: Department of Cardiology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand; University of Queensland School of Medicine, Brisbane, QLD 4006, Australia.
authors: Wandy
authors: W
authors: Chan
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Chris M
authors: CM
authors: Florkowski
authors: Department of Anatomical Pathology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand.
authors: Martin
authors: M
authors: Sage
authors: Department of Life Sciences, Brunel University London, Uxbridge, Middlesex UB8 3PH, UK.
authors: Thomas
authors: T
authors: Höfken
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Bader
authors: B
authors: Alhaddad
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Laura S
authors: LS
authors: Kremer
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Robert
authors: R
authors: Kopajtich
authors: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
authors: René G
authors: RG
authors: Feichtinger
authors: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
authors: Wolfgang
authors: W
authors: Sperl
authors: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, 6500HB Nijmegen, the Netherlands.
authors: Richard J
authors: RJ
authors: Rodenburg
authors: Department of Neonatology UKBB Bruderholz, University Children's Hospital Basel, 4056 Basel, Switzerland.
authors: Jean Claude
authors: JC
authors: Minet
authors: Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
authors: Angus
authors: A
authors: Dobbie
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Tim M
authors: TM
authors: Strom
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors: Thomas
authors: T
authors: Meitinger
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand; Department of Pathology, University of Otago, Christchurch 8140, New Zealand. Electronic address: peter.george@cdhb.health.nz.
authors: Peter M
authors: PM
authors: George
authors: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors: Colin A
authors: CA
authors: Johnson
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Robert W
authors: RW
authors: Taylor
authors: Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors: Holger
authors: H
authors: Prokisch
authors: Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand; Department of Pathology, University of Otago, Christchurch 8140, New Zealand.
authors: Kit
authors: K
authors: Doudney
authors: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria. Electronic address: h.mayr@salk.at.
authors: Johannes A
authors: JA
authors: Mayr
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000473:pathology; D000431:Ethanol / Q000009:adverse effects; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D005355:Fibrosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D043564:Inorganic Pyrophosphatase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012640:Seizures; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D000431:Ethanol; D043564:Inorganic Pyrophosphatase; C509848:PPA2 protein, human