Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA

Walter H A Kahr, Anna Savoia, Fred G. Pluthero, Ling Li, Hilary Christensen, Daniela De Rocco, Chanchai Traivaree, Sheila E. Butchart, Julie Curtin, Elliott J. Stollar, Julie D. Forman-Kay, Victor S. Blanchette

Research output: Contribution to journalArticlepeer-review


Heterozygous mutations in MYH9, which encodes non-muscle myosin heavy chain IIA (MHC-IIA), result in autosomal dominant inherited MYH9-related disorders characterised by macrothrombocytopenia, granulocyte inclusions, variable sensorineural deafness, cataracts and nephritis. MHC-IIA is assembled into a complex consisting of two pairs of light chains and two heavy chains, where the latter contain a neck region, SH3-like, motor and rod domains. We describe a patient with a Trp33Cys missense mutation in the SH3-like domain of MHC-IIA. Abnormal platelet function was observed using platelet aggregometry with the agonists epinephrine and adenosine diphosphate (ADP). Patient granulocytes and megakaryocytes, but not platelets, contained abnormal MHC-IIA inclusions visualised by confocal im-munofluorescence or electron microscopy. Megakaryocytes grown in culture were smaller and contained hypolobulated nuclei compared to controls. Bone marrow-derived megakaryocytes revealed a preponderance of immature forms, the presence of structurally diverse inclusion bodies, and frequent emperipolesis as assessed by electron microscopy. Platelets and leukocytes contained indistinguishable amounts of total MHCIIA determined by immunoblotting. Molecular modelling studies indicated that mutation of Trp33 destabilises the interface between the SH3-like and motor domain of MHC-IIA, which is close to previously described motor domain mutations, implying an important structural and/or functional role for this region in MHC-IIA.

Original languageEnglish
Pages (from-to)1241-1250
Number of pages10
JournalThrombosis and Haemostasis
Issue number6
Publication statusPublished - Dec 2009


  • Emperipolesis
  • Inherited macrothrombocytopenia
  • Megakaryocytes
  • MYH9-related disorder
  • Myosin IIA

ASJC Scopus subject areas

  • Hematology


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