A New Form of Familial Thrombocytopenia Associated with a Mutation of Cytochrome C

Abstract number: P1523

Morison¹ IM, Cheong¹ PL, Holyoake² AJ, Fichelson³ S, Cramer³ EM, Cheesman¹ EJ

¹¹University of Otago, Dunedin, New Zealand ¹¹University of Otago, Dunedin, New Zealand ²²Pacific Edge Biotechnology Ltd, Dunedin, New Zealand ³³Institut Cochin, INSERM 567, Paris, France

We describe a new form of autosomal dominant thrombocytopenia. Affected members of the family belong to four generations, are asymptomatic and show no other haematologic, congenital or degenerative abnormalities. Several individuals have undergone major surgery without bleeding complications. The platelet counts of the 26 affected family members varied from 73 to 148 × 10⁹/L. The mean platelet volume was normal and the platelets showed mildly impaired agonist-induced aggregation. After establishing genetic linkage to a 1.12 Mb region on chromosome 7p15, DNA sequencing revealed a single base change in exon 2 of cytochrome c, along with four other polymorphisms. The cytochrome c mutation results in substitution of a conserved glycine at position 41 by a serine residue. This is the first reported mutation or polymorphism of human cytochrome c. Electron microscopic study of bone marrow megakaryocytes showed direct release of platelets into the marrow space, and in vitro culture of CD34+ cells from an affected individual showed markedly early and enhanced platelet production, suggesting dysregulated production and release of platelets. Purified mutant cytochrome c shows intact haem binding, and redox titration studies were normal. Results from cell-free assays will be presented indicating the pathway by which the mutant protein causes thrombocytopenia.