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Biochim Biophys Acta. 2014 Feb;1842(2):269-74. doi: 10.1016/j.bbadis.2013.12.002. Epub 2013 Dec 8.

Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics.

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Department of Medical Sciences, University of Trieste, Trieste, Italy.
Clinical Genetics Unit, Dept. of Woman and Child Health, University of Padova, IRP Città della Speranza, Padova, Italy.
Department of Life Sciences, University of Parma, Parma, Italy.
Division of Pediatric Hematology/Oncology, University of Catania, Catania, Italy.
National Institute for Medical Research, London, NW71AA, UK.
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Internal Medicine, University of Pavia-IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
Department of Medical Sciences, University of Trieste, Trieste, Italy; Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy. Electronic address:


Inherited thrombocytopenias are heterogeneous diseases caused by at least 20 genes playing different role in the processes of megakaryopoiesis and platelet production. Some forms, such as thrombocytopenia 4 (THC4), are very rare and not well characterized. THC4 is an autosomal dominant mild thrombocytopenia described in only one large family from New Zealand and due to a mutation (G41S) of the somatic isoform of the cytochrome c (CYCS) gene. We report a novel CYCS mutation (Y48H) in patients from an Italian family. Similar to individuals carrying G41S, they have platelets of normal size and morphology, which are only partially reduced in number, but no prolonged bleeding episodes. In order to determine the pathogenetic consequences of Y48H, we studied the effects of the two CYCS mutations in yeast and mouse cellular models. In both cases, we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia.


Apoptosis; Cellular bioenergetics; Cytochrome c; Thrombocytopenia THC4

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