A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia

• Published in: Nature genetics Vol. 40; no. 4; pp. 387 - 389
• Main Authors: da Silva Tatley, Fernanda M, Weeks, Robert J, Wilbanks, Sigurd M, Fagerlund, Robert D, Smith, Mark P, Davies, Stefan M K, Capron, Claude, Ledgerwood, Elizabeth C, Fichelson, Serge, Holyoake, Andrew J, Pippig, Diana A, Morison, Ian M, Cheesman, Emma J, Ludgate, Mathew W, Coker, Melanie S A, Bockett, Nicholas A, Cheong, Pak Leng, Hughes, Gillian, Lo, Alexandra, Cramer Bordé, Elisabeth M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2008; Nature Publishing Group
• Subjects: Ageing, cell death; Agriculture; Animal Genetics and Genomics; Apoptosis; Apoptosis - physiology; Apoptotic Protease-Activating Factor 1 - metabolism; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; brief-communication; Cancer Research; Cell physiology; Complications and side effects; Cytochrome; Cytochromes; Cytochromes c - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Hematologic and hematopoietic diseases; Human Genetics; Humans; Male; Medical sciences; Megakaryocytes - metabolism; Megakaryocytes - pathology; Molecular and cellular biology; Mutation; Mutation - genetics; Oxidation-Reduction; Pedigree; Physiological aspects; Physiology; Platelet Count; Platelet diseases and coagulopathies; Risk factors; Serine - chemistry; Serine - genetics; Signal Transduction; Thrombocytopenia; Thrombocytopenia - etiology; Thrombocytopenia - pathology; New Zealand; Cytochrome c; Human; Thrombocytopenia; Platelet; Hemopathy; Mutation; Apoptosis
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.103

We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis.