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

CRISPR/Cas9 CYCS caspase cytochrome c mitochondria thrombocytopenia

Journal

British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544

Informations de publication

Date de publication:
27 Aug 2024
Historique:
received: 14 05 2024
accepted: 26 07 2024
medline: 28 8 2024
pubmed: 28 8 2024
entrez: 27 8 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1111/bjh.19694 PMID: 39191490
pubmed: 39191490
doi: 10.1111/bjh.19694
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

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

Informations de copyright

© 2024 Masaryk University. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

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Auteurs

Jiří Štika (J)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Michaela Pešová (M)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Kateřina Staňo Kozubík (KS)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Magdalena Skalníková (M)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.

Lenka Dostálová (L)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.

Tomáš Loja (T)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.

Lenka Radová (L)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Veronika Palušová (V)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia.

Kamila Réblová (K)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Zuzana Vrzalová (Z)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Ivona Blaháková (I)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Jakub Trizuljak (J)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Stjepan Uldrijan (S)

Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia.

Jan Blatný (J)

Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Pediatric Hematology and Biochemistry, University Hospital Brno, Brno, Czechia.

Michal Šmída (M)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Šárka Pospíšilová (Š)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.

Michael Doubek (M)

Center of Molecular Medicine, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czechia.
ORCID: 0000-0002-1269-6282

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