A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation study
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Published on: April 1, 2019
Jiří Štika1,2, Michaela Pešová1,3, Kateřina Staňo Kozubík1,2,3
1Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Insights
A novel variant in the CYCS gene causes inherited thrombocytopenia-4 (THC4) with progressive platelet decline. This variant impacts cytochrome c expression, mitochondrial respiration, and caspase activity, offering insights into THC4 pathogenesis.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- The CYCS gene is crucial for mitochondrial function and is highly conserved.
- Pathogenic variants in CYCS can lead to thrombocytopenia-4 (THC4), a bleeding disorder.
- Understanding CYCS variant effects is vital for diagnosing and treating inherited thrombocytopenia.
Purpose of the Study:
- To identify and characterize a novel CYCS gene variant associated with thrombocytopenia in a Czech family.
- To investigate the molecular mechanisms by which this CYCS variant affects platelet production and function.
- To explore the potential role of caspase dysregulation in CYCS-related thrombocytopenia.
Main Methods:
- Segregation analysis of the novel CYCS variant (c.59C>T) in a three-generation family.
- CRISPR/Cas9 gene editing to introduce the variant into the MEG-01 megakaryoblast cell line.
- Comprehensive analysis of cellular functions including adhesion, respiration, protein expression, and caspase activity.
Main Results:
- The novel CYCS variant (p.(Thr20Ile)) segregates with dominant thrombocytopenia (THC4) with normal platelet size/morphology and progressive decline across generations.
- The variant reduces CYCS expression, enhances mitochondrial respiration, and increases CD9 cell surface antigen expression.
- The variant significantly inhibits caspase activation, a novel finding potentially linked to thrombopoiesis dysregulation.
Conclusions:
- A new CYCS variant causes inherited thrombocytopenia-4 with unique molecular consequences.
- Dysregulated caspase activity due to the CYCS variant may contribute to the pathogenesis of thrombocytopenia.
- These findings advance the understanding of inherited thrombocytopenia and may inform future therapeutic strategies.
Abstract:
The CYCS gene is highly evolutionarily conserved, with only a few pathogenic variants that cause thrombocytopenia-4 (THC4). Here, we report a novel CYCS variant NM_018947.6: c.59C>T [NP_061820.1:p.(Thr20Ile)] segregating with thrombocytopenia in three generations of a Czech family. The phenotype of the patients corresponds to THC4 with platelets of normal size and morphology and dominant inheritance. Intriguingly, a gradual decline in platelet counts was observed across generations. CRISPR/Cas9-mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast cell line (MEG-01). Subsequently, the adhesion, shape, size, ploidy, viability, mitochondrial respiration, cytochrome c protein (CYCS) expression, cell surface antigen expression and caspase activity were analysed in cells carrying the studied variant. Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial respiration and the expression of CD9 cell surface antigen. Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants. Some reports indicate that caspases may be involved in thrombopoiesis; thus, the observed dysregulation of caspase activity might contribute to thrombocytopenia. The findings significantly enhance our understanding of the molecular mechanisms underlying inherited thrombocytopenia and may have implications for diagnosis, prognosis and future targeted therapies.
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