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

doi:10.1160/TH09-02-0119

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 102(06): 1241-1250
DOI: 10.1160/TH09-02-0119

Platelets and Blood Cells

Schattauer GmbH

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

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

²Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada

,

Anna Savoia

³Medical Genetics, Department of Reproductive and Developmental Sciences, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, University of Trieste, Italy

,

Fred G. Pluthero

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

²Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada

,

Ling Li

²Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada

,

Hilary Christensen

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

,

Daniela De Rocco

³Medical Genetics, Department of Reproductive and Developmental Sciences, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, University of Trieste, Italy

,

Chanchai Traivaree

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

,

Sheila E. Butchart

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

,

Julie Curtin

⁴Department of Haematology, The Children’s Hospital, Westmead, New South Wales, Australia

,

Elliott J. Stollar

⁵Program in Molecular Structure & Function, The Hospital for Sick Children, Toronto, Ontario, Canada

,

Julie D. Forman-Kay

⁵Program in Molecular Structure & Function, The Hospital for Sick Children, Toronto, Ontario, Canada

,

Victor S. Blanchette

¹Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

› Author Affiliations

Abstract

Summary

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 immunofluorescence 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.

Keywords

Inherited macrothrombocytopenia - MYH9-related disorder - megakaryocytes - emperipolesis - myosin IIA

Full Text

References

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