Johannes A. Mayr, Tobias B. Haack, Elisabeth Graf, Franz A

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Lack of the Mitochondrial Protein Acylglycerol Kinase Causes Sengers Syndrome Johannes A. Mayr, Tobias B. Haack, Elisabeth Graf, Franz A. Zimmermann, Thomas Wieland, Birgit Haberberger, Andrea Superti-Furga, Janbernd Kirschner, Beat Steinmann, Matthias R. Baumgartner, Isabella Moroni, Eleonora Lamantea, Massimo Zeviani, Richard J. Rodenburg, Jan Smeitink, Tim M. Strom, Thomas Meitinger, Wolfgang Sperl, Holger Prokisch The American Journal of Human Genetics Volume 90, Issue 2, Pages 314-320 (February 2012) DOI: 10.1016/j.ajhg.2011.12.005 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Distribution of the AGK Mutations and Their Consequences on AGK Structure of AGK (A) and localization of identified mutations. AGK (B) was not detectable with immunoblot analysis (primary AGK antibody [1:1,000; rabbit polyclonal; GTX107413, Genetex]) in myoblasts form affected individual 54027 and in fibroblasts of individuals 60453 and 60455. (C1) Myoblast control. (C2 and C3) Fibroblast controls. The American Journal of Human Genetics 2012 90, 314-320DOI: (10.1016/j.ajhg.2011.12.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Deficiency in ATP Synthesis and ANT in Sengers Syndrome The increased ratio of [1-14C]pyruvate + malate + CCCP over [1-14C]pyruvate + malate + ADP oxidation (A) in affected individual 54027 (filled square) versus controls (triangles) indicates a deficiency in ATP synthesis. A decreased amount of ANT (B) was detected with immunoblot analysis in skeletal muscle and in differentiated myoblasts (C) of affected individual 54027. Primary antibodies and their conditions are as follows: ANT antibody (1:1,000; mouse monoclonal; MSA02, Mitosciences) and SDHA (1:30,000; mouse monoclonal; MS204, Mitosciences). The American Journal of Human Genetics 2012 90, 314-320DOI: (10.1016/j.ajhg.2011.12.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Potential Role of AGK in the Mitochondrial Lipid Metabolism Abbreviations are as follows: AGK, acylglycerol kinase; CDS, CDP-diacylglycerol synthase; PGS, phosphatidylglycerophosphate synthase; PTPMT, phosphatidylglycerol-phosphate phosphatase; CRLS, cardiolipin synthase; ANT, adenine nucleotide translocator; DAK, diacylglycerol kinase; GPAT, glycerol-3-phosphate acyltransferase; LPAAT, 1-acylglycerol-3-phosphate O-acyltransferase; G3P, glycerol 3-phosphate; LPA, lyso-phosphatidic acid; PA, phosphatidic acid; DAG, diacylglycerol; TAG, triacylglycerol; PL, phospholipid; CDP-DAG, cytidine diphosphate diacylglycerol; PGP, phosphatidylglycerol-phosphate; PG, phosphatidylglyceroll; CL, cardiolipin; ER, endoplasmic reticulum; OMM, outer mitochondrial membrane; and IMM, inner mitochondrial membrane. The American Journal of Human Genetics 2012 90, 314-320DOI: (10.1016/j.ajhg.2011.12.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions