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

Lookup NU author(s): Dr Charlotte Alston, Professor Bobby McFarlandORCiD, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Kennedy H, Haack TB, Hartill V, Matakovic L, Baumgartner ER, Potter H, Mackay R, Alston CL, O'Sullivan S, McFarland R, Connolly G, Gannon C, King R, Mead S, Crozier I, Chan W, Florkowski CM, Sage M, Hofken T, Alhaddad B, Kremer LS, Kopajtich R, Feichtinger RG, Sperl W, Rodenburg RJ, Minet JC, Dobbie A, Strom TM, Meitinger T, George PM, Johnson CA, Taylor RW, Prokisch H, Doudney K, Mayr JA

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2016

Volume: 99

Issue: 3

Pages: 674-682

Print publication date: 01/09/2016

Online publication date: 11/08/2016

Acceptance date: 27/06/2016

Date deposited: 26/07/2017

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2016.06.027

DOI: 10.1016/j.ajhg.2016.06.027


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Funding

Funder referenceFunder name
Maia Health Foundation
Lily Foundation
UK NHS Highly Specialised Commissioners
Vereinigung zur Forderung padiatrischer Forschung und Fortbildung
01GM1207E-Rare project GENOMIT
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research
09/JTASir Jules Thorn Award
317433EC FP7-PEOPLE-ITN Mitochondrial European Educational Training (MEET) Project (GA)
A-12/01/005-SPEAdd-On-Project of the PMU-FFF
FKZ 01ZX1405CBMBF through the Juniorverbund in der Systemmedizin "mitOmics"
FS/13/32/30069British Heart Foundation
G0601943Medical Research Council (UK) Centre for Translational Muscle Disease Research
NIHR-HCS-D12-03-04National Institute for Health Research (NIHR)
mitoNET 01GM1113CGerman Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders
Z76010017300BMBF through the DZHK (German Centre for Cardiovascular Research)
Z56010015300BMBF through the DZHK (German Centre for Cardiovascular Research)

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