期刊
CLINICAL GENETICS
卷 94, 期 6, 页码 548-553出版社
WILEY
DOI: 10.1111/cge.13423
关键词
CYCS; cytochrome c; hemophilia A; loss of function mutation; mitochondria; thrombocytopenia
资金
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Japan Agency for Medical Research and Development [JP18dm 0107090JP18ek0109280JP18ek0109301JP18ek0109348JP18kk020500]
- Japan Science and Technology Agency
- Japan Society for the Promotion of Science [17K15630JP15K10367JP16H05160JP16H05357JP16H06254JP17H01539JP17H06994JP17K10080]
- Takeda Science Foundation
We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the alpha-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants.
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