Background: Autosomal dominant giant platelet syndrome (GPS) is characterized by thrombocytopenia, giant platelets, and Dhle-like inclusion bodies in leukocytes.Previous studies suggest relatively preserved platelet structure and function, implicating impaired megakaryocyte fragmentation.This study aimed to identify myosin heavy chain 9 (MYH9) mutations in Korean patients with GPS and to define the associated clinical, molecular and functional characteristics.Methods: After detailed personal and family history taking, peripheral blood smears were reviewed for platelet size, count, and leukocyte inclusions.MYH9 mutations were analyzed in peripheral blood mononuclear cells by direct sequencing of selected exons or complementary DNA (cDNA).Computer-assisted structural modeling was performed to evaluate the functional consequences of identified mutations.Results: Twenty-two affected individuals from six unrelated families were diagnosed with hereditary macrothrombocytopenia consistent with GPS.The median platelet count was 59,000/L, and the mean platelet volume was markedly increased (17.8 fL).Platelets ranged from approximately half to 1.5 times the size of red blood cells.Dhle-like inclusions were observed in 25-33% of leukocytes in four families.Extrahematologic manifestations included hearing impairment (family with Ile1816Val) and renal involvement, ranging from mild proteinuria to chronic renal failure requiring renal transplantation (family with Lys373Asn).Five families harbored MYH9 mutations-Arg1933Ter, Trp33Cys (novel), Lys373Asn, Ile1816Val, and Arg1165Cys-located in exons 40, 1, 10, 37, and 26, respectively; mutations segregated with affected status.Biochemical analysis revealed decreased MYH9 in soluble fractions with increased insoluble pellets; Trp33Cys and Lys373Asn produced aberrant approximately 140 kDa bands in addition to the normal 224 kDa band.Modeling localized Trp33Cys to the proximal myosin head region implicated in actin interaction.Conclusion: Five GPS-associated MYH9 mutations were identified, including a novel Trp33Cys variant.Altered MYH9 solubility and disturbed protein-protein interactions may contribute to disease pathogenesis.
Hwang et al. (Thu,) studied this question.