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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 McFarland, 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

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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