Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia
| Autor: | Deborah Whitehorn, Mattia Frontini, Ernest Turro, Luigi Grassi, Cedric Ghevaert, Albert Koulman, Tadbir K. Bariana, Veerle Labarque, Keith Gomez, Willem H. Ouwehand, Benjamin Jenkins, Jessica Heremans, Olga Shamardina, Mara De Reys, Chris Van Geet, Sofia Papadia, Denis Seyres, Frances Burden, Daniel Greene, Nihr BioResource, Chantal Thys, Kathleen Freson |
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| Přispěvatelé: | Seyres, Denis [0000-0002-2066-6980], Shamardina, Olga [0000-0003-4994-2157], Papadia, Sofia [0000-0002-9222-3812], Koulman, Albert [0000-0001-9998-051X], Ouwehand, Willem [0000-0002-7744-1790], Ghevaert, Cedric [0000-0002-9251-0934], Frontini, Mattia [0000-0001-8074-6299], Turro Bassols, Ernest [0000-0002-1820-6563], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Platelets
Blood Platelets Male induced pluripotent stem cell Ceramide Cellular differentiation Induced Pluripotent Stem Cells Biology Article megakaryocyte Platelet Biology & its Disorders 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Erythrokeratodermia variabilis Megakaryocyte medicine Animals Humans Metabolomics Myelofibrosis Induced pluripotent stem cell Child Cells Cultured Zebrafish Sphingolipids proplatelet Cell Differentiation Hematology medicine.disease Prognosis Sphingolipid Thrombocytopenia Pedigree Alcohol Oxidoreductases medicine.anatomical_structure chemistry Mutation Cancer research Female sphingolipid Stem cell Megakaryocytes 030215 immunology |
| Zdroj: | Haematologica |
| Popis: | Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder erythrokeratodermia variabilis et progressiva-4 Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia, and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalization of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organization during megakaryopoiesis and proplatelet formation. ispartof: HAEMATOLOGICA vol:104 issue:5 pages:1036-1045 ispartof: location:Italy status: published |
| Databáze: | OpenAIRE |
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