Kennedy, H, Haack, TB, Hartill, V et al. (32 more authors) (2016) Sudden Cardiac Death due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2. American Journal of Human Genetics. ISSN 0002-9297
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Opthalmology and Neurosciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Sep 2016 14:21 |
Last Modified: | 05 Oct 2017 16:26 |
Published Version: | http://dx.doi.org/10.1016/j.ajhg.2016.06.027 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ajhg.2016.06.027 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105431 |