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A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation study

J. Štika, M. Pešová, KS. Kozubík, M. Skalníková, L. Dostálová, T. Loja, L. Radová, V. Palušová, K. Réblová, Z. Vrzalová, I. Blaháková, J. Trizuljak, S. Uldrijan, J. Blatný, M. Šmída, Š. Pospíšilová, M. Doubek

. 2024 ; 205 (6) : 2450-2458. [pub] 20240827

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003290

Grantová podpora
NU20-08-00137 Ministry of Health, Czech Republic
LX22NPO5102 European Union-Next Generation EU
MUNI/A/1224/2022 Masaryk University
MUNI/11/SUP/22/2020 Masaryk University
CZ.02.1.01/0.0/0.0/16_026/0008448 European Regional Development Fund
FNBr,65269705 Ministry of Health, Czech Republic-conceptual development of research organization

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.

Citace poskytuje Crossref.org

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