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.

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

“…Our findings stand in stark contrast with studies suggesting that megakaryocytes deliberately undergo apoptosis in order to facilitate platelet shedding [5][6][7][8][9][10]48 . One explanation for the discrepancy might be that megakaryocytes have evolved their own unique apoptotic pathways, which utilize effectors other than BAK, BAX and Caspase-8.…”

“…In cultured megakaryocytes, overexpression of BCL-X L 7 or treatment with the pan-caspase inhibitor z-VAD.fmk 8,9 was reported to reduce proplatelet formation. Conversely, in a human family with thrombocytopenia, premature platelet release into the BM was ascribed to the expression of a variant form of Cytochrome c with enhanced proapoptotic activity 10 . These observations suggest a critical, cell autonomous, role for the intrinsic pathway in platelet biogenesis.…”

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

“…Mks showed premature and enhanced in vitro PPF and signs of ectopic platelet release were found at examination of BM biopsy of one patient [2].…”

“…Morison and colleagues [2] reported a large family with AD thrombocytopenia caused by a mutation in CYCS increasing the proapoptotic activity of cytochrome c. Increased intrinsic apoptosis in Mks was responsible for premature PPF within BM and consequent ineffective platelet production. Mks showed premature and enhanced in vitro PPF and signs of ectopic platelet release were found at examination of BM biopsy of one patient [2].…”

“…In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified [1][2][3][4][5][6][7][8][9], and this led to the recognition of 6 novel nosographic entities [1]. To date, ITs encompass 20 forms caused by mutations of 21 genes ( Table 1).…”