Subscribe to RSS
Heavy chain myosin 9-related disease (MYH9-RD): Neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder
26 August 2009
Accepted after minor revision: 06 February 2009
22 November 2017 (online)
MYH9-related disease (MYH9-RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9-RD is caused by mutations of MYH9, the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9-RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9-RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9-RD.
- 1 Kelley MJ, Jawien W, Ortel TL. et al. Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May- Hegglin anomaly. Nat Genet 2000; 26: 106-108.
- 2 The May-Hegglin/Fechtner Syndrome Consortium.. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nat Genet 2000; 26: 103-105.
- 3 Seri M, Pecci A, Di Bari F. et al. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine 2003; 82: 203-215.
- 4 Pecci A, Malara A, Badalucco S. et al. Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost 2009; 102: 90-96.
- 5 Pecci A, Panza E, Pujol-Moix N. et al. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 2008; 29: 409-417.
- 6 Noris P, Spedini P, Belletti S. et al. Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May-Hegglin anomaly): clinical and laboratory findings. Am J Med 1998; 104: 355-360.
- 7 Rocca B, Laghi F, Zini G. et al. Fechtner syndrome: report of a third family and literature review. Br J Haematol 1993; 85: 423-426.
- 8 Pujol-Moix N, Muniz-Diaz E, Moreno-Torres ML. et al. Sebastian platelet syndrome. Two new cases in a Spanish family. Ann Hematol 1991; 62: 235-237.
- 9 Epstein CJ, Sahud MA, Piel CF. et al. Hereditary macrothrombocytopathia, nephritis and deafness. Am J Med 1972; 52: 299-310.
- 10 Hegglin R. Gleichzeitige konstitutionelle Veranderungen an Neutrophilen und Thrombocyten. Helv Med Acta 1945; 12: 439-440.
- 11 May R. Leukozyteneinschlusse. Dtsch Arch Klin Med 1909; 96: 1-6.
- 12 Kunishima S, Matsushita T, Yoshihara T. et al. First description of somatic mosaicism in MYH9 disorders. Br J Haematol 2005; 128: 360-365.
- 13 Savoia A, Balduini CL. MYH9/-Related Disorders in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle, 1997–2008. Available at http://www.genetests.org.
- 14 Balduini CL, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy. Haematologica 2002; 87: 860-880.
- 15 Kunishima S, Kojima T, Matsushita T. et al. Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome). Blood 2001; 97: 1147-1149.
- 16 Kunishima S, Matsushita T, Kojima T. et al. Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of sub-cellular localization with MYH9 mutations. Lab Invest 2003; 83: 115-122.
- 17 Pecci A, Noris P, Invernizzi R. et al. Immunocytochemistry for the heavy chain of the non-muscle myosin IIA as a diagnostic tool for MYH9-related disorders. Br J Haematol 2002; 117: 164-167.
- 18 Kunishima S, Matsushita T, Shiratsuchi M. et al. Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness. Eur J Haematol 2005; 74: 1-5.
- 19 Heath KE, Campos-Barros A, Toren A. et al. 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.
- 20 Noris P, Klersy C, Zecca M. et al. Platelet size distinguishes between inherited macrothrombocytopenias and immune thrombocytopenia. J Thromb Haemost 2009; 07: 2131-2136.
- 21 Jantunen E. Inherited giant platelet disorders. Eur J Haematol 1994; 53: 191-196.
- 22 Savoia A, Balduini CL, Savino M. et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood 2001; 97: 1330-1335.
- 23 Borrione AC, Zanellato AM, Giuriato L. et al. Nonmuscle and smooth muscle myosin isoforms in bovine endothelial cells. Exp Cell Res 1990; 190: 1-10.
- 24 Pecci A, Canobbio I, Balduini A. et al. Pathogenetic mechanisms of haematological abnormalities of patients with MYH9 mutations. Hum Mol Genet 2005; 14: 3169-3178.
- 25 Kunishima S, Matsushita T, Hamaguchi M. et al. Identification and characterization of the first large deletion of the MYH9 gene associated with MYH9 disorders. Eur J Haematol 2008; 80: 540-544.
- 26 Kunishima S, Yoshinari M, Nishio H. et al. Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations. Eur J Haematol 2007; 78: 220-226.
- 27 Kunishima S, Matsushita T, Kojima T. et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macro-thrombocytopenia with leukocyte inclusions. J Hum Genet 2001; 46: 722-729.
- 28 Conti MA, Even-Ram S, Liu C. et al. Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice. J Biol Chem 2004; 279: 41263-41266.
- 29 Franke JD, Dong F, Rickoll WL. et al. Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. Blood 2005; 105: 161-169.
- 30 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.
- 31 De Rocco D, Heller PG, Girotto G. et al. MYH9 related disease: A novel missense Ala95Asp mutation of the MYH9 gene. Platelets 2009; 20: 598-602.
- 32 De Rocco D, Pujol-Moix N, Pecci A. et al. Identification of the first duplication in MYH9-related disease: A hot spot for hot unequal crossing-over within exon 24 of the MYH9 gene. Eur J Med Genet 2009; 52: 191-194.
- 33 Pecci A, Panza E, De Rocco D. et al. MYH9 related disease: four novel mutations of the tail domain of myosin-9 correlating with a mild clinical phenotype. Eur J Haematol. 2009 prepub online doi:10.1111/j.1600-0609.2009.01398.x.