Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2 PMID: 27523597

ADC Targets in Oncology

2026-04-10

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2

Am J Hum Genet. 2016 Sep 1;99(3):674-682. doi: 10.1016/j.ajhg.2016.06.027.

Hannah Kennedy ¹ , Tobias B Haack ² , Verity Hartill ³ , Lavinija Mataković ⁴ , E Regula Baumgartner ⁵ , Howard Potter ⁶ , Richard Mackay ⁶ , Charlotte L Alston ⁷ , Siobhan O'Sullivan ⁸ , Robert McFarland ⁷ , Grainne Connolly ⁹ , Caroline Gannon ¹⁰ , Richard King ⁶ , Scott Mead ⁶ , Ian Crozier ¹¹ , Wandy Chan ¹² , Chris M Florkowski ⁶ , Martin Sage ¹³ , Thomas Höfken ¹⁴ , Bader Alhaddad ² , Laura S Kremer ² , Robert Kopajtich ² , René G Feichtinger ⁴ , Wolfgang Sperl ⁴ , Richard J Rodenburg ¹⁵ , Jean Claude Minet ¹⁶ , Angus Dobbie ¹⁷ , Tim M Strom ² , Thomas Meitinger ¹⁸ , Peter M George ¹⁹ , Colin A Johnson ³ , Robert W Taylor ⁷ , Holger Prokisch ² , Kit Doudney ¹ , Johannes A Mayr ²⁰

Affiliations

1. Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand; Department of Pathology, University of Otago, Christchurch 8140, New Zealand.
2. 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.
3. Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
4. Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
5. Metabolic Unit, University Children's Hospital Basel (UKBB), 4056 Basel, Switzerland.
6. Molecular Pathology Laboratory, Canterbury Health Laboratories, Canterbury District Health Board, Christchurch 8140, New Zealand.
7. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
8. Department of Metabolic Paediatrics, Royal Hospital for Sick Children, Belfast BT12 6BA, UK.
9. Department of Clinical Biochemistry, Royal Victoria Hospital, Belfast BT12 6BA, UK.
10. Department of Pathology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
11. Department of Cardiology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand.
12. Department of Cardiology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand; University of Queensland School of Medicine, Brisbane, QLD 4006, Australia.
13. Department of Anatomical Pathology, Christchurch Hospital, Canterbury District Health Board, Christchurch 8140, New Zealand.
14. Department of Life Sciences, Brunel University London, Uxbridge, Middlesex UB8 3PH, UK.
15. Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, 6500HB Nijmegen, the Netherlands.
16. Department of Neonatology UKBB Bruderholz, University Children's Hospital Basel, 4056 Basel, Switzerland.
17. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
18. 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.
19. 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: [email protected].
20. Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria. Electronic address: [email protected].

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.