Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation.
MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations of MYH9, the gene for the heavy chain of myosin-IIA. Pathogenesis of thrombocytopenia of MYH9-RD is unknown. Recent studies in mice demonstrated that myosin-IIA is an inhibitor of proplatelet formation (PPF), and suggested that it could be involved in the suppression of PPF exerted by megakaryocyte adhesion to type I collagen, which regulates the timing of platelet release within bone marrow. However, the consequences on PPF of the heterozygous mutations causative of the MYH9-RD have never been investigated. We studied the in-vitro PPF by megakaryocytes obtained from four patients carrying the p.D1424N or the p.R1933X mutations. We demonstrated that MYH9-RD megakaryocytes completely lose the physiologic suppression of proplatelet extension exerted by interaction with type I collagen, thus supporting the hypothesis that a premature platelet release within bone marrow contributes to pathogenesis of MYH9-related thrombocytopenia. Moreover, proplatelets extended by MYH9-RD megakaryocytes presented a significant defect in branching in secondary processes (p=0.001) and formed a significantly lower number of proplatelet tips (p=0.005). Since platelets are assembled at the level of proplatelet tips, this defect could further contribute to pathogenesis of thrombocytopenia of MYH9-RD patients.
Pecci
Alessandro
A
Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy. alessandro.pecci@unipv.it
Malara
Alessandro
A
Badalucco
Stefania
S
Bozzi
Valeria
V
Torti
Mauro
M
Balduini
Carlo L
CL
Balduini
Alessandra
A
D000328:Adult; D001792:Blood Platelets / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D020409:Molecular Motor Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D017354:Point Mutation; D013234:Stem Cells / Q000473:pathology*; D013921:Thrombocytopenia / Q000235:genetics* / Q000473:pathology*
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains