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

Abstract

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.

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Figure 1: Defective platelet formation but normal platelet lifespan.
Figure 2: G41S variant of cytochrome c has enhanced proapoptotic activity but normal redox activity.

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Acknowledgements

We acknowledge funding support from Lottery Health Research, the University of Otago, the HS & JC Anderson Charitable Trusts and from the Health Research Council of New Zealand. We thank C. Porteous, T. Kleffmann, V. Jalbert and A. Yacia for expert technical assistance, M. Murphy, M. Hampton and A. Reeve for discussions, C. Beresford for clinical assessment, G. Pielak for the cytochrome c plasmid and the affected family for their extraordinary contribution.

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Contributions

I.M.M. and E.J.C. initiated the study, recruited and evaluated participants; A.J.H., M.W.L., F.M.d.S.T., M.S.A.C. and N.A.B. performed linkage studies, haplotype refinement and sequencing; M.P.S., E.M.C., S.F. and C.C. performed functional platelet and megakaryocyte studies and electron microscopy; P.L.C., R.J.W., E.C.L., A.L., S.M.K.D., G.H., S.M.W., R.D.F. and D.A.P. expressed the proteins and performed functional and structural studies; and I.M.M., E.C.L., E.M.C. and S.M.W. wrote the paper.

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Correspondence to Ian M Morison.

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Competing interests

A.J.H. was a full-time employee of Pacific Edge Biotechnology Ltd., which owns the intellectual property associated with G41S cytochrome c, when performing experiments and contributing to this paper.

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Supplementary Methods, Supplementary Figures 1–4, Supplementary Tables 1 and 2 (PDF 2718 kb)

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Morison, I., Cramer Bordé, E., Cheesman, E. et al. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet 40, 387–389 (2008). https://doi.org/10.1038/ng.103

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