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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):1036-1045
Platelet Biology & its Disorders
Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia
Tadbir K. Bariana,1.2.3,4 Veerle Labarque,5 Jessica Heremans, 5 Chantal Thys,4,5 Mara De Reys,5 Daniel Greene,3,4,6,7 Benjamin Jenkins,8 Luigi Grassi,3,4,6,7 Denis Seyres,3,4,6,7 Frances Burden,3,4,6 Deborah Whitehorn,3,4,6,
Olga Shamardina,3,4,6 Sofia Papadia,3,4,6 Keith Gomez,1,2,4 NIHR BioResource,4 Chris Van Geet,4,5 Albert Koulman,8 Willem H. Ouwehand,3,4,6,9,10
Cedric Ghevaert,
Mattia Frontini, 4,5
3,4,6,9 3,4,6,7 Ernest Turro
3,6,9 and Kathleen Freson
1Department of Haematology, University College London, UK; 2The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, UK; 3Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, UK; 4NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, UK; 5Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Belgium; 6NHS Blood and Transplant, Cambridge Biomedical Campus, UK; 7Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, UK; 8NIHR Biomedical Research Centre Core Metabolomics and Lipidomics Laboratory, University of Cambridge, Cambridge Biomedical Campus, UK; 9British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Cambridge University Hospitals, Cambridge Biomedical Campus, UK and 10Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
ABSTRACT
Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihy- drosphingosine reductase is an essential enzyme for de novo sphin- golipid 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 pheno- typic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocy- topenia, anemia, and minimal skin involvement. We report a novel phe- notype 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 megakary- ocyte 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 expres- sion of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in pro- platelet 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.
Correspondence:
KATHLEEN FREESON kathleen.freson@med.kuleuven.be
Received: August 17, 2018. Accepted: November 19, 2018. Pre-published: November 22, 2018.
doi:10.3324/haematol.2018.204784
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/1036
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