ZFIN ID: ZDB-PUB-181127-53
Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia
Bariana, T.K., Labarque, V., Heremans, J., Thys, C., De Reys, M., Greene, D., Jenkins, B., Grassi, L., Seyres, D., Burden, F., Whitehorn, D., Shamardina, O., Papadia, S., Gomez, K., NIHR BioResource, Van Geet, C., Koulman, A., Ouwehand, W.H., Ghevaert, C., Frontini, M., Turro, E., Freson, K.
Date: 2018
Source: Haematologica   104(5): 1036-1045 (Journal)
Registered Authors:
Keywords: Platelets, induced pluripotent stem cell, megakaryocyte, proplatelet, sphingolipid
MeSH Terms:
  • Alcohol Oxidoreductases/deficiency*
  • Alcohol Oxidoreductases/genetics
  • Animals
  • Blood Platelets/metabolism
  • Blood Platelets/pathology*
  • Cell Differentiation
  • Cells, Cultured
  • Child
  • Female
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Induced Pluripotent Stem Cells/pathology*
  • Male
  • Megakaryocytes/metabolism
  • Megakaryocytes/pathology*
  • Metabolomics
  • Mutation
  • Pedigree
  • Prognosis
  • Sphingolipids/metabolism*
  • Thrombocytopenia/etiology*
  • Thrombocytopenia/metabolism
  • Thrombocytopenia/pathology
  • Zebrafish
PubMed: 30467204 Full text @ Haematologica
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 normalisation 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 organisation during megakaryopoiesis and proplatelet formation.