Congenital Thrombocytopenia and Cytochrome c Mutation: A Matter of Birth and Death

Abstract

Thrombocytopenia (TP) Cargeeg is a unique autosomal dominant disorder, affecting a seven-generation family, caused by cytochrome c (CYCS) mutation that dysregulates platelet formation. The CYCS mutation in this disorder is a glycine 41 replacement by serine, which yields a cytochrome c variant with enhanced apoptotic pathway activity in vitro. The deregulated apoptosis in this disorder affects megakaryocytes (MK) during platelet formation, leading to early and ectopic platelet release in the bone marrow (BM). Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of physiological apoptosis in most cells. The pathophysiology of this unique inherited TP, with unaltered platelet survival and normal MK content in the BM, has implications for physiological and pathological mechanisms altering MK apoptosis, with implications for other unexplained thrombocytopenic disorders.

Thrombocytopenia - apoptosis - megakaryocytes - cytochrome c - CYSC mutation

REFERENCES

• 1 Avecilla S T, Hattori K, Heissig B et al.. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis.  Nat Med. 2004;  10 (1) 64-71
• 2 Zauli G, Vitale M, Falcieri E et al.. In vitro senescence and apoptotic cell death of human megakaryocytes.  Blood. 1997;  90 (6) 2234-2243
• 3 Mason K D, Carpinelli M R, Fletcher J I et al.. Programmed anuclear cell death delimits platelet life span.  Cell. 2007;  128 (6) 1173-1186
• 4 Kile B T. The role of the intrinsic apoptosis pathway in platelet life and death.  J Thromb Haemost. 2009;  7 (Suppl 1) 214-217
• 5 Cramer E M, Norol F, Guichard J et al.. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand.  Blood. 1997;  89 (7) 2336-2346
• 6 Dunois-Lardé C, Capron C, Fichelson S, Bauer T, Cramer-Bordé E, Baruch D. Exposure of human megakaryocytes to high shear rates accelerates platelet production.  Blood. 2009;  114 (9) 1875-1883
• 7 Junt T, Schulze H, Chen Z et al.. Dynamic visualization of thrombopoiesis within bone marrow.  Science. 2007;  317 (5845) 1767-1770
• 8 Ouzegdouh Y, Momeux L, Cramer-Borde E. Vascular Niche and Platelet Production: Stromal Cells Inhibit Proplatelet and Platelet Formation by Human Megakaryocytes (MK), Whereas Endothelial Cells Are Permissive.  ASH Annual Meeting Abstracts. 2010;  116 (21) 402
• 9 Morison I M, Cramer Bordé E M, Cheesman E J et al.. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia.  Nat Genet. 2008;  40 (4) 387-389
• 10 Finsterer J, Mitochondriopathies F J. Eur J Neurol. 2004;  11 (3) 163-186
• 11 Sabri S, Foudi A, Boukour S et al.. Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment.  Blood. 2006;  108 (1) 134-140
• 12 Riedl S J, Salvesen G S. The apoptosome: signalling platform of cell death.  Nat Rev Mol Cell Biol. 2007;  8 (5) 405-413
• 13 Pop C, Salvesen G S. Human caspases: activation, specificity, and regulation.  J Biol Chem. 2009;  284 (33) 21777-21781
• 14 Banci L, Bertini I, Rosato A, Varani G. Mitochondrial cytochromes c: a comparative analysis.  J Biol Inorg Chem. 1999;  4 (6) 824-837
• 15 Liptak M D, Fagerlund R D, Ledgerwood E C, Wilbanks S M, Bren K L. The proapoptotic G41S mutation to human cytochrome c alters the heme electronic structure and increases the electron self-exchange rate.  J Am Chem Soc. 2011;  133 (5) 1153-1155
• 16 Yuan S, Yu X, Topf M, Ludtke S J, Wang X, Akey C W. Structure of an apoptosome-procaspase-9 CARD complex.  Structure. 2010;  18 (5) 571-583
• 17 Yu T, Wang X, Purring-Koch C, Wei Y, McLendon G L. A mutational epitope for cytochrome C binding to the apoptosis protease activation factor-1.  J Biol Chem. 2001;  276 (16) 13034-13038
• 18 Solary E, Giordanetto F, Kroemer G. Re-examining the role of cytochrome c in cell death.  Nat Genet. 2008;  40 (4) 379-380
• 19 Olteanu A, Patel C N, Dedmon M M et al.. Stability and apoptotic activity of recombinant human cytochrome c.  Biochem Biophys Res Commun. 2003;  312 (3) 733-740
• 20 Savoia A, Noris P, Perrotta S et al.. Absence of CYCS mutations in a large Italian cohort of patients with inherited thrombocytopenias of unknown origin.  Platelets. 2009;  20 (1) 72-73
• 21 Chipuk J E, Moldoveanu T, Llambi F, Parsons M J, Green D R. The BCL-2 family reunion.  Mol Cell. 2010;  37 (3) 299-310
• 22 De Botton S, Sabri S, Daugas E et al.. Platelet formation is the consequence of caspase activation within megakaryocytes.  Blood. 2002;  100 (4) 1310-1317
• 23 Clarke M C, Savill J, Jones D B, Noble B S, Brown S B. Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death.  J Cell Biol. 2003;  160 (4) 577-587
• 24 Ogilvy S, Metcalf D, Print C G, Bath M L, Harris A W, Adams J M. Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival.  Proc Natl Acad Sci U S A. 1999;  96 (26) 14943-14948
• 25 Bouillet P, Metcalf D, Huang D C et al.. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.  Science. 1999;  286 (5445) 1735-1738
• 26 Kaluzhny Y, Yu G, Sun S et al.. BclxL overexpression in megakaryocytes leads to impaired platelet fragmentation.  Blood. 2002;  100 (5) 1670-1678
• 27 Josefsson E C, James C, Henley K J et al.. Megakaryocytes Possess a Functional Intrinsic Apoptosis Pathway That Must Be Restrained In Order to Survive and Produce Platelets.  ASH Annual Meeting Abstracts. 2010;  116 (21) 550