Five (un)easy pieces: the MYH9-related giant platelet syndromes.

cytoplasmic inclusions were first noted by May almost 100 years ago.7 FTNS is distinguished by the additional clinical features of high-tone sensorineural deafness, cataracts, and nephritis. APSM is similar to FTNS except that Döhle-like inclusions have not been described and it is distinguished from the classical X-linked form of Alport syndrome in that COL4A5 gene mutations are not present. Finally, EPS is similar to both FTNS and APSM, except that cataracts and leukocyte inclusions have not been described. Recently, we and others have mapped the genetic defect underlying all five of these syndromes to chromosome 22q11-138-11 and established that all are caused by mutations in the non-muscle myosin heavy chain IIA gene.12-15 Hence, MHA, SBS, FTNS, EPS, and APSM represent a class of allelic disorders with phenotypic diversity and we have proposed the name myosin heavy chain 9 syndrome to encompass them.14 MYH9 is expressed in many different tissues, including platelets, leukocytes, kidney, and cochlea, is part of a hexameric enzyme complex, which binds actin, has ATPase activity, and is required for motor activity.16 The genetic studies suggest that mutations in MYH9 are involved in the pathogenesis of macrothrombocytopenia, bleeding, deafness, cataracts, and nephritis. Obviously, therefore, MYH9 must also play a role in the normal development and maintenance of these cells, processes and structures. How then is this balance maintained? Most likely, the understanding of the pathogenic mechanisms will be driven by biochemical extension of the genetic findings. A possible biological basis to the bleeding defect in MHA and SBS has now been described. DiPumpo et al.,6 present novel findings suggesting a linkage between MYH9 mutations and an alteration in platelet surface expression of the GPIb-V-IX complex. Specifically, following size fractionation of platelets from genetically defined MHA and SBS affected subjects, the authors demonstrated that 7/8 individuals had decreased Five (un)easy pieces: the MYH9-related giant platelet syndromes