MYH9-related disease (MYH9-RD) is an autosomal dominant disorder caused by mutations in the MYH9 gene. It is characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like granulocyte inclusions. In this study we report 10 unrelated patients with MYH9-RD in whom the following seven MYH9 gene mutations were found: W33R, p.Q1443_K1445dup, R702H, D1424N, E1841K, R1933X, and E1945X (the first two were novel mutations). The region of the MYH9 mutation determines in some regards the phenotype, but clinical expression can vary between individuals with the same mutation. The neutrophil inclusion bodies of two patients were too small to be detected, but could be found with immunofluorescence staining. Immunoblotting analysis revealed that the calculated NMMHC-IIA/β-actin ratio for MYH9-RD neutrophils was 39% of normal controls. Kidney biopsy showed segmental glomerulosclerosis and NMMHC-IIA expression was decreased in podocytes. This disease is not as rare as originally thought. In any individual with persistent macrothrombocytopenia and no response to corticosteroids and immunosuppressive agents, even if neutrophil inclusions were inconspicuous in routine staining, MYH9-RD should be suspected.

Sekine T, Konno M, Sasaki S, Moritani S, Miura T, Wong WS, Nishio H, Nishiguchi T, Ohuchi MY, Tsuchiya S, Matsuyama T, Kanegane H, Ida K, Miura K, Harita Y, Hattori M, Horita S, Igarashi T, Saito H, Kunishima S: Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease. Kidney Int 2010;78:207–214.
Heath KE, Campos-Barros A, Toren A, Rozenfeld-Granot G, Carlsson LE, Savige J, Denison JC, Gregory MC, White JG, Barker DF, Greinacher A, Epstein CJ, Glucksman MJ, Martignetti JA: Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet 2001;69:1033–1045.
Althaus K, Greinacher A: MYH9-related platelet disorders. Semin Thromb Hemost 2009;35:189–203.
Toren A, Rozenfeld-Granot G, Rocca B, Epstein CJ, Amariglio N, Laghi F, Landolfi R, Brok-Simoni F, Carlsson LE, Rechavi G, Greinacher A: Autosomal-dominant giant platelet syndromes: a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11–13. Blood 2000;96:3447–3451.
Kunishima S, Kojima T, Tanaka T, Kamiya T, Ozawa K, Nakamura Y, Saito H: Mapping of a gene for May-Hegglin anomaly to chromosome 22q. Hum Genet 1999;105:379–383.
Sellers JR: Myosins: a diverse superfamily. Biochim Biophys Acta 2000;1496:3–22.
Wei Q, Adelstein RS: Conditional expression of a truncated fragment of nonmuscle myosin IIA alters cell shape but not cytokinesis in Hela cells. Mol Biol Cell 2000;11:3617–3627.
Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS: Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain IIA in mice. J Biol Chem 2004;279:41263–41266.
Niederman R, Pollard TD: Human platelet myosin. 2. In vitro assembly and structure of myosin filaments. J Cell Biol 1975;67:72–92.
Pecci A, Malara A, Badalucco S, Bozzi V, Torti M, Balduini CL, Balduini A: Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost 2009;102:90–96.
Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, Inoue C, Kamiya T, Saito H: Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations. Lab Invest 2003;83:115–122.
Kunishima S, Yoshinari M, Nishio H, Ida K, Miura T, Matsushita T, Hamaguchi M, Saito H: Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations. Eur J Haematol 2007;78:220–226.
Kunishima S, Hamaguchi M, Saito H: Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood 2008;111:3015–3023.
Ghiggeri GM, Caridi G, Magrini U, Sessa A, Savoia A, Seri M, Pecci A, Romagnoli R, Gangarossa S, Noris P, Sartore S, Necchi V, Ravazzolo R, Balduini CL: Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome). Am J Kidney Dis 2003;41:95–104.
Kunishima S, Kojima T, Matsushita T, Tanaka T, Tsurusawa M, Furukawa Y, Nakamura Y, Okamura T, Amemiya N, Nakayama T, Kamiya T, Saito H: Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome). Blood 2001;97:1147–1149.
Kelley MJ, Jawien W, Ortel TL, Korczak JF: Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. Nat Genet 2000;26:106–108.
Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, Ghiggeri GM, Ravazzolo R, Savino M, Del Vecchio M, d’Apolito M, Iolascon A, Zelante LL, Savoia A, Balduini CL, Noris P, Magrini U, Belletti S, Heath KE, Babcock M, Glucksman MJ, Aliprandis E, Bizzaro N, Desnick RJ, Martignetti JA: Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes: the May-Heggllin/Fechtner Syndrome consortium. Nat Genet 2000;26:103–105.
Balduini CL, Pecci A, Savoia A: Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 2010;154:161–174.
Kahr WH, Savoia A, Pluthero FG, Li L, Christensen H, De Rocco D, Traivaree C, Butchart SE, Curtin J, Stollar EJ, Forman-Kay JD, Blanchette VS: Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA. Thromb Haemost 2009;102:1241–1250.
Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A: Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 2008;29:409–417.
Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, Inoue M, Jung Y, Mamiya S, Matsumoto K, Miyajima Y, Zhang G, Ruan C, Saito K, Song KS, Yoon HJ, Kamiya T, Saito H: Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet 2001;46:722–729.
De Rocco D, Pujol-Moix N, Pecci A, Faletra F, Bozzi V, Balduini CL, Savoia A: Identification of the first duplication in MYH9-related disease: a hot spot for unequal crossing-over within exon 24 of the MYH9 gene. Eur J Med Genet 2009;52:191–194.
Kunishima S, Matsushita T, Hamaguchi M, Saito H: Identification and characterization of the first large deletion of the MYH9 gene associated with MYH9 disorders. Eur J Haematol 2008;80:540–544.
Pecci A, Canobbio I, Balduini A, Stefanini L, Cisterna B, Marseglia C, Noris P, Savoia A, Balduini CL, Torti M: Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet 2005;14:3169–3178.
Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, Mumford A, Heller PG, Noris P, De Groot MR, Giani M, Freddi P, Scognamiglio F, Riondino S, Pujol-Moix N, Fabris F, Seri M, Balduini CL, Pecci A: Heavy chain myosin 9-related disease (MYH9-RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Thromb Haemost 2010;103:826–832.
Althaus K, Greinacher A: MYH-9 related platelet disorders: strategies for management and diagnosis. Transfus Med Hemoth 2010;37:260–267.
Arrondel C, Vodovar N, Knebelmann B, Grunfeld JP, Gubler MC, Antignac C, Heidet L: Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J Am Soc Nephrol 2002;13:65–74.
Hao J, Kunishima S, Guo X, Hu R, Gao W: A large family with MYH9 disorder caused by E1841K mutation suffering from serious kidney and hearing impairment and cataracts. Ann Hematol 2012;91:1147–1148.
Shao XR, Li JZ, Ma J, Zhan ZM, Liang H, She XN, Lu HL, Wang LC, Jia CM, Wu LJ, Jin MH, Chen LJ: Clinical and molecular-biological study of a May-Hegglin anomaly family. Zhonghua Xue Ye Xue Za Zhi 2004;25:548–551.
Zhang G, Yi Y, Xu M, Ling Z: Identification of nonmuscle mysin heavy chain 9 gene mutation in a May-Hegglin anomaly family. Zhonghua Yi Xue Za Zhi 2002;82:918–920.
Pecci A, Granata A, Fiore CE, Balduini CL: Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome). Nephrol Dial Transplant 2008;23:2690–2692.
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