title: Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA.
abstract: Heterozygous mutations in MYH9, which encodes non-muscle myosin heavy chain IIA (MHC-IIA), result in autosomal dominant inherited MYH9-related disorders characterised by macro-thrombocytopenia, 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 MHC-IIA 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.
authors: Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. walter.kahr@sickkids.ca
authors: Walter H A
authors: WH
authors: Kahr
authors: Anna
authors: A
authors: Savoia
authors: Fred G
authors: FG
authors: Pluthero
authors: Ling
authors: L
authors: Li
authors: Hilary
authors: H
authors: Christensen
authors: Daniela
authors: D
authors: De Rocco
authors: Chanchai
authors: C
authors: Traivaree
authors: Sheila E
authors: SE
authors: Butchart
authors: Julie
authors: J
authors: Curtin
authors: Elliott J
authors: EJ
authors: Stollar
authors: Julie D
authors: JD
authors: Forman-Kay
authors: Victor S
authors: VS
authors: Blanchette
mesh_terms: D019943:Amino Acid Substitution; D001791:Blood Platelet Disorders / Q000097:blood / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D017124:Conserved Sequence; D005260:Female; D006098:Granulocytes / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D020409:Molecular Motor Proteins / Q000737:chemistry* / Q000235:genetics*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry* / Q000235:genetics*; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics; D018909:src Homology Domains
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains