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A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia
Author(s) -
Uchiyama Yuri,
Yanagisawa Kunio,
Kunishima Shinji,
Shiina Masaaki,
Ogawa Yoshiyuki,
Nakashima Mitsuko,
Hirato Junko,
Imagawa Eri,
Fujita Atsushi,
Hamanaka Kohei,
Miyatake Satoko,
Mitsuhashi Satomi,
Takata Atsushi,
Miyake Noriko,
Ogata Kazuhiro,
Handa Hiroshi,
Matsumoto Naomichi,
Mizuguchi Takeshi
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13423
Subject(s) - mutation , biology , genetics , mitochondrial respiratory chain , cytochrome c , exon , gene , exome sequencing , in silico , respiratory chain , microbiology and biotechnology , mitochondrion
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 α‐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.