Hannah Kennedy, Tobias B. Haack, Verity Hartill, Lavinija Mataković, E

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Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2 Hannah Kennedy, Tobias B. Haack, Verity Hartill, Lavinija Mataković, E. Regula Baumgartner, Howard Potter, Richard Mackay, Charlotte L. Alston, Siobhan O’Sullivan, Robert McFarland, Grainne Connolly, Caroline Gannon, Richard King, Scott Mead, Ian Crozier, Wandy Chan, Chris M. Florkowski, Martin Sage, Thomas Höfken, Bader Alhaddad, Laura S. Kremer, Robert Kopajtich, René G. Feichtinger, Wolfgang Sperl, Richard J. Rodenburg, Jean Claude Minet, Angus Dobbie, Tim M. Strom, Thomas Meitinger, Peter M. George, Colin A. Johnson, Robert W. Taylor, Holger Prokisch, Kit Doudney, Johannes A. Mayr The American Journal of Human Genetics Volume 99, Issue 3, Pages 674-682 (September 2016) DOI: 10.1016/j.ajhg.2016.06.027 Copyright © 2016 The Author(s) Terms and Conditions

Figure 1 Pedigree Structure, PPA2 Genomic Organization Conservation, and Family 1 Variant Modeling (A) Pedigrees of four families identified with mutations in PPA2 (GenBank: NM_176869.2) encoding the mitochondrial inorganic pyrophosphatase. Individuals with a question mark have not been tested. Mutations found in more than one family are colored. (B) Location of mutations within the gene, and phylogenetic conservation of the predicted missense mutations. (C) Space fill model showing position of p.Pro228 at boundary of dimers and p.Glu172 in the active site produced in CN3D with reference PDB: 1M38. (D) Left: Structural model of one molecule of PPA2 showing the position of four mutations in folded structure (red). Residues that are known to be critical to PPA2 function in S. cerevisiae are highlighted in yellow.19 Right: Space fill of the PPA2 active site showing three substitutions are located at the surface of the active site. Models produced using Swiss-PdbViewer20 (with reference PDB: 1M38). The American Journal of Human Genetics 2016 99, 674-682DOI: (10.1016/j.ajhg.2016.06.027) Copyright © 2016 The Author(s) Terms and Conditions

Figure 2 Cardiac Fibrosis in PPA2 Deficiency (A) Affected individual P3, post mortem section through left ventricle showing a virtually circumferential lamina of scarring in midmyocardium with focal subendocardial involvement. Fibrosis is marked by arrows. (B and C) Low-power (B) (bar equals 1 mm) and high-power (C) (bar equals 25 μm) microscopy of the posterior freewall of the left ventricle showing prominent midmyocardial loose fibrosis in P3 (hematoxylin and eosin staining). (D) Cardiac MRI showing prominent midmyocardial fibrosis in affected individual P4 (at 25 years of age), marked by arrows. The American Journal of Human Genetics 2016 99, 674-682DOI: (10.1016/j.ajhg.2016.06.027) Copyright © 2016 The Author(s) Terms and Conditions

Figure 3 Inorganic Pyrophosphatase Activity in Fibroblast Mitochondria and Recombinant Enzymes (A and B) Activity of inorganic pyrophosphatase in different fibroblast mitochondria isolations from affected individuals (P) P5, P7, and P9 compared to 14 control subjects (C) at different PPi concentrations and either (A) 0.5 mmol/L MgCl2 or (B) 3.0 mmol/L MgCl2. (C) Inhibition of inorganic pyrophosphatase in fibroblast mitochondria from affected individual P5 (red squares) and three control subjects (black circles) incubated at 0.5 mmol/L MgCl2 and different CaCl2 concentrations and either 0.1 mmol/L PPi or 0.01 mmol/L PPi (small insert). (D) Pyrophosphatase activity of equal amounts of recombinant proteins at different PPi concentrations. (E) Protein amount of recombinant PPA2 protein was adjusted by western blot analysis and silver staining (Figure S9). ∗p < 0.01, ∗∗p < 0.0001 in Student’s unpaired t test. The error bars in this graph indicate the standard error of the mean. The American Journal of Human Genetics 2016 99, 674-682DOI: (10.1016/j.ajhg.2016.06.027) Copyright © 2016 The Author(s) Terms and Conditions