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Compound heterozygous c-Mpl mutations in a child with congenital amegakaryocytic thrombocytopenia: Functional characterization and a review of the literature

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Published copy (DOI)


  • Norma E. Fox
  • Rose Chen
  • Ian Hitchcock
  • Jennifer Keates-Baleeiro
  • Haydar Frangoul
  • Amy E. Geddis


Publication details

JournalExperimental hematology
DateE-pub ahead of print - 12 Jan 2009
DatePublished (current) - Apr 2009
Issue number4
Number of pages9
Pages (from-to)495-503
Early online date12/01/09
Original languageEnglish


OBJECTIVE: To genetically and functionally characterize mutations of c-Mpl that lead to thrombocytopenia in a child with congenital amegakaryocytic thrombocytopenia.

MATERIALS AND METHODS: We identified two c-Mpl mutations in a child with clinical features of congenital amegakaryocytic thrombocytopenia, one a previously described mutation in the extracellular domain (R102P) and the other a novel mutation leading to truncation of the receptor after the box 1 homology domain (541Stop). Cell line models were created to examine the ability of the mutant receptors to signal in response to thrombopoietin and thrombopoietin-like agonists.

RESULTS: Data from cell-line models indicate that c-Mpl R102P does not support significant signaling in response to thrombopoietin due to impaired trafficking of the mutant receptor to the cell surface. Alternative thrombopoietic agents do not circumvent this block to signaling, likely due to the inaccessibility of the receptor. In addition, previous data indicate that c-Mpl 541Stop does not support intracellular signaling due to the loss of critical intracellular domains.

CONCLUSIONS: This case demonstrates two different mechanisms by which c-Mpl mutations can impair thrombopoietin signaling, and suggests that mutations in the extracellular domain will not be rescued by c-Mpl agonists if they interfere with normal receptor expression.

    Research areas

  • Base Sequence, Cell Line, Child, Preschool, Female, Glycosylation, Heterozygote, Humans, Megakaryocytes, Molecular Sequence Data, Mutation, Protein Binding, Receptors, Thrombopoietin, Signal Transduction, Thrombocytopenia

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