IntroductionFamilial macrothrombocytopenias with leukocyte inclusion bodies are a group of rare autosomal dominant disorders characterized by mild bleeding symptoms, giant platelets, and Döhle-like inclusion bodies in peripheral blood granulocytes. These disorders, which include the May-Hegglin anomaly (MHA; OMIM [Online Mendelian Inheritance in Man], #155100), Sebastian syndrome (SBS; OMIM, #605249), Fechtner syndrome (FTNS; OMIM, #153640), and Epstein syndrome (EPS; OMIM, #153650) all have largely overlapping phenotypes but were previously considered as separate clinical entities. [1][2][3][4] Biochemical analysis of platelets from patients with MHA revealed no abnormalities in the function of these cells, 5,6 leading to the hypothesis that the hematologic phenotype in patients may result from a deficit in the demarcation membranes in megakaryocytes prior to platelet formation. 7 MHA and SBS are distinguished from each other by small differences in their inclusion bodies revealed by electron microscopy examination. 8 FTNS and EPS, however, manifest a number of nonhematologic traits similar to those observed in Alport syndrome cases, such as nephritis, high-tone sensorineural deafness, and bilateral cataracts, all of which are present with variable expressivity. 1,9,10 The discovery that the genetic loci for all of these syndromes mapped to chromosome 22q12.3 Ϫq13.2, 11-13 and the identification of mutations in the MYH9 gene for each of them, showed that this group of pathologies represent allelic variations of a single genetic disorder. [14][15][16][17][18] MYH9, a 5.8-kb (kilobase) mRNA transcript, encodes for the nonmuscle myosin heavy chain A (also known as NMMHC-A), a large cytoplasmic protein that forms part of the myosin II hexameric complex. 19,20 MYH9 consists of an adenosine triphosphatase (ATPase) globular head domain at its N-terminus and a C-terminal tail domain that forms a coiled coil structure on dimerization.The function of nonmuscular myosin II (MYH9 containing) has not been fully characterized. 21 It has been shown to form clusters of minifilaments in the cytoplasm, which concentrate in stress fibers near the periphery of cells and in the cleavage furrow of dividing cells. 22 Nonmuscular myosin is involved in processes such as phagocytosis 23 and cytokinesis, and in the latter it is thought to drive constriction of the cleavage furrow, as shown elegantly in Dictyostelium discoideum, where myosin IInull cells fail to divide. 24 These data are consistent with the originally proposed disease mechanism of impaired thrombopoiesis as a result of defects in cytoskeleton rearrangement in megakaryocytes, 7 although this is still a poorly understood process.The MYH9 gene has subsequently been found to be involved in 2 further disorders, DFNA17 (OMIM, #603622), an autosomal 25 and APSM (OMIM, #153650), a variant of Alport syndrome with macrothrombocytopenia. 16 To date, 20 different disease-associated mutations have been found in the MYH9 gene, covering the range of phenotypes represented by the 6 clin...

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