MYH9

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Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene.[1][2]

Non-muscle myosin IIA (NM IIA) is expressed in most cells and tissues where it participates in a variety of processes requiring contractile force, such as cytokinesis, cell migration, polarization and adhesion, maintenance of cell shape, and signal transduction. Myosin IIs are motor proteins that are part of a superfamily composed of more than 30 classes.[3][4][5] Class II myosins include muscle and non-muscle myosins that are organized as hexameric molecules consisting of two heavy chains (230 kDa), two regulatory light chains (20 KDa) controlling the myosin activity, and two essential light chains (17 kDa), which stabilize the heavy chain structure.[6][7][8][9][10]

Gene and protein structure

MYH9 is a large gene spanning more than 106 kilo base pairs on chromosome 22q12.3. It is composed of 41 exons with the first ATG of the open reading frame localized in exon 2 and the stop codon in exon 41. It encodes non-muscle myosin heavy chain IIA (NMHC IIA), a protein of 1,960 amino acids. Consistent with its wide expression in cells and tissues, the promoter region of MYH9 is typical of housekeeping genes having no TATA box but high GC content, with multiple GC boxes. MYH9 is a well-conserved gene through evolution. The mouse ortholog (Myh9) is localized in a syntenic region on chromosome 15 and has the same genomic organization as that of the human gene. It encodes a protein of the same length, with 97.1% amino acid identity with the human MYH9 protein.[11]

Like all class II myosins, the two NMHC IIAs dimerize producing an asymmetric molecular structure recognizable by two heads and a tail domain: the N-terminal half of each heavy chain generates the head domain, which consists of the globular motor domain and the neck domain, and the C-terminal halves of the two heavy chains together form the tail domain.[12] The motor domain, which is organized into four subdomains (SH3-like motif, the upper and the lower 50kDa subdomains, and the converter region) connected by flexible linkers,[13] interacts with filamentous actin to generate force through magnesium-dependent hydrolysis of ATP. The neck acts as a lever arm that amplifies the movement produced by conformational changes of the motor domain, and is the binding site for the light chains through two IQ motifs. The tail domain is fundamental for both dimerization of the heavy chains and formation of NM IIA functional filaments. Two heavy chains dimerize through the tail domain forming a long alpha-helical coiled-coil rod composed of typical heptad repeats. Dimers self-associate though the coiled-coil rods to form myosin filaments. The tail domain ends at the C-terminus with a 34-residue non-helical tailpiece.[10][12]

Regulation of NM IIA structure and function

There are three paralogs of non-muscle myosin II (NM II), NM IIA, IIB, and IIC, with each having the heavy chain encoded on a different chromosome. All three paralogs appear to bind the same or very similar light chains and share basic properties as to structure and activation, but all three play distinct roles during vertebrate development and adulthood (for general reviews on NM IIs, see [7][9][10]). All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement. In addition, they can form bipolar filaments which can interact with and exert tension on actin filaments. These properties provide the basis for all NM II functions. The path to myosin filament formation, which is shared by NM II and smooth muscle myosin, starts with a folded inactive conformation of the NM II monomer which, upon phosphorylation of the 20 KDa light chain unfolds the molecule to produce a globular head region followed by an extended alpha-helical coiled-coil tail.[14][15][16][17] The tail portion of the molecule can interact with other NM IIA hexamers to form bipolar filaments composed of 14-16 molecules.

Phosphorylation of the 20 KDa light chains on Serine 19 and Threonine 18 by a number of different kinases, but most prominently by Rho-dependent kinase and/or by the calcium-calmodulin-dependent myosin light chain kinase, not only linearizes the folded structure but removes the inhibition imposed on the MgATPase activity due to the folded conformation. In addition to phosphorylation of the 20 KDa light chains, the NMHC IIs can also be phosphorylated, but the sites phosphorylated differ among the paralogs.[6] In most cases phosphorylation of NMHC IIA can act to either dissociate the myosin filaments or to prevent filament formation.

In addition to phosphorylation, NM IIA filament assembly and localization can be modulated by interaction with other proteins including S100A4 and Lethal giant larvae (Lgl1). The former is a calcium binding protein and is also known as metastatin, a well-characterized metastatic factor. S100A4 expression is associated with enhanced cell migration through maintenance of cell polarization and inhibition of cell turning.[18][19] Similar to heavy chain phosphorylation, in vitro binding of S100A to the carboxy-terminal end of the NM IIA coiled-coil region prevents filament formation and S100A4 binding to previously formed filaments promotes filament disassembly. The tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro.[20][21] In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions. Other proteins that are known to interact with NM IIA include the actin binding protein tropomyosin 4.2 [22] and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1).[23]

Functions specific to NM IIA

NM IIA plays a major role in early vertebrate development. Ablation of NM IIA in mice results in lethality by embryonic day (E) 6.5 due to abnormalities in the visceral endoderm which is disorganized due to a loss of E-cadherin mediated cell-cell adhesions.[24] Lacking a normal polarized columnar layer of endoderm, the abnormal visceral endoderm of NM IIA knockout embryos fails to support the critical step of gastrulation. However, the development of a normal functioning visceral endoderm does not specifically depend on NM IIA since its function can be restored by genetically replacing the NMHC IIA with cDNA encoding NMHC II B (or NMHC IIC) that is under control of the NMHC IIA promoter.[25] These “replacement” mice have a normal visceral endoderm and continue to proceed through gastrulation and undergo organogenesis. However, they die when they fail to develop a normal placenta. Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion. Moreover mutant p.R702C NM IIA mice show similar defects in placental formation [26] and mice specifically ablated for NM IIA in the mouse trophoblast-lineage cells demonstrate placental defects similar to mice in which NMHC IIA is genetically replaced by NMHC IIB.[27] There are significant differences in the relative abundance of the three NM II paralogs in various cells and tissues. However, NM IIA appears to be the predominant paralog in both tissues and cells in humans and mice. Mass spectroscopy analysis of the relative abundance of NMHC IIs in mouse tissues and human cell lines [28] shows that NM IIA is predominant, although tissues like the heart vary from cell to cell; myocardial cells contain only NM IIB but NM IIA is more abundant in the non-myocyte cells. NM IIB is predominant in most parts of the brain and spinal cord but NM IIA is relatively more abundant in most other organs and cells lines. Both NM IIA and IIB are expressed early in development with NM IIC expression starting at E 11.5 in mice. Not only do most cells contain more than one paralog but there is evidence that the paralogs can co-assemble intracellularly into heterotypic filaments in a variety of settings in cultured cells.[29][30][31]

Clinical significance

MYH9-related disease. Mutations in MYH9 cause a Mendelian autosomal-dominant disorder known as MYH9-related disease (MYH9-RD).[32][33][34][35] All affected individuals present congenital hematological alterations consisting in thrombocytopenia, platelet macrocytosis, and inclusions of the MYH9 protein in the cytoplasm of granulocytes. Most patients develop one or more non-congenital manifestations, including sensorineural deafness, kidney damage, presenile cataracts, and/or elevation of liver enzymes.[35][36][37] The term MYH9-RD encompasses four syndromic pictures that were considered for many years as distinct disorders, namely May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. After the identification of MYH9 as the gene responsible for all of these entities, it was recognized that they actually represent different clinical presentations of the same disease, now known as MYH9-RD or MYH9 disorder.[34] MYH9-RD is a rare disease: prevalence is estimated around 3:1,000,000. The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders. The disease has been reported worldwide and there is no evidence of variation in prevalence across ethnic populations.[38]

Thrombocytopenia can result in a variable degree of bleeding tendency. The majority of patients have no spontaneous bleeding or only mild cutaneous bleeding (easy bruising) and are at risk of significant hemorrhages only after surgery or other invasive procedures, deliveries, or trauma. Some patients have spontaneous mucosal bleeding, such as menorrhagia, epistaxis, and gum bleeding.[35][36] Severe and life-threatening hemorrhages are not frequent. Platelets of MYH9-RD patients are characterized by a very large size: platelets larger than red blood cells (called "giant platelets") are always present at the examination of peripheral blood smears.[34][39] Granulocyte inclusions of the NMHC IIA may be evident at the analysis of blood films after conventional staining as cytoplasmic basophilic (light blue) inclusions, called "Döhle-like bodies".[34][35] More than 50% of MYH9-RD patients develop sensorineural hearing loss.[36] Severity of the hearing impairment is greatly variable, as it ranges from a mild hearing defect that occurs in mid or advanced age to a progressive hearing loss that is evident in the first years of life and rapidly evolves to severe deafness.[40] Kidney damage occurs in about 25% of patients. It presents with proteinuria and often progresses to kidney failure, which, in its most severe forms, may require dialysis and/or kidney transplantation.[36] Around 20% of patients develop presenile cataracts. About 50% of MYH9-RD patients present chronic or intermittent elevation of liver transaminases or gamma-glutamyl transferases: this alteration appears to be benign, as no patients showed evolution to liver dysfunction.[37]

Diagnosis of MYH9-RD is confirmed by the identification of the NMHC IIA inclusions in granulocytes through an immunofluorescence assay on peripheral blood smears and/or by the detection of the causative mutation through mutational screening of the MYH9 gene.[41][42][43][44]

In most cases, MYH9-RD is caused by missense mutations affecting the head or tail domain of the NMHC IIA. Nonsense or frameshift alterations resulting in the deletion of a C-terminal fragment of the NMHC IIA (17 to 40 residues) are involved in approximately 20% of families. In-frame deletions or duplications have been identified in a few cases.[36][41][45] The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic.[42] Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism.[46][47][48]

The incidence and the severity of the non-congenital manifestations of MYH9-RD correlate with the specific MYH9 mutation. The recent definition of genotype-phenotype correlations allows prediction of the clinical evolution of the disease in most cases.[36][49] Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions.[36][39][50]

Within a phase 2 trial, eltrombopag, an agonist of the thrombopoietin receptor, significantly increased platelet count in 11 out of 12 patients affected with MYH9-RD.[51] ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement.[52][53] Cochlear implantation is effective in restoring hearing function in MYH9-RD patients with severe/profound deafness.[54]

Role of MYH9 variants in other human diseases. Evidence obtained in animals indicates that MYH9 acts as a tumor suppressor gene. Silencing of Myh9 in the epithelial cells in mice was associated with the development of squamous cell carcinoma (SCC) of the skin and the head and neck.[55] In another mouse model, ablation of Myh9 in the tongue epithelium led to the development of tongue SCC.[56] In mice predisposed to invasive lobular breast carcinoma (ILBC) because of E-cadherin ablation, the inactivation of Myh9 led to the development of tumors recapitulating the features of human ILBC.[57] Some observations suggest that defective MYH9 expression is associated with oncogenesis and/or tumor progression in human SCC and ILBC, thus also supporting a role for MYH9 as a tumor suppressor in humans.[55][57]

Genetic variations in MYH9 may be involved in predisposition to chronic kidney disease (CKD). A haplotype of MYH9 (haplotype E1) was previously associated with the increased prevalence of glomerulosclerosis[58] and non-diabetic end stage renal disease[59] in African Americans and in Hispanic Americans.[60] However, subsequent studies showed that this association is explained by strong linkage disequilibrium with two haplotypes (haplotypes G1 and G2) in the neighboring APOL1 gene.[61][62][63] Nevertheless, some studies suggest an association of single-nucleotide polymorphisms in MYH9 with CKD that appears to be independent of the linkage with APOL1 G1 and G2.[64][65][66]

Inherited MYH9 mutations may be responsible for non-syndromic hearing loss.[67][68][69]

Other model organisms

Model organisms have been used in the study of MYH9 function. A conditional knockout mouse line, called Myh9tm1a(EUCOMM)Wtsi[74][75] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[76][77][78]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[72][79] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[72] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[72]

Other interactions

MYH9 has been shown to interact with PRKCE.[80]

See also

References

  1. ↑ Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L (August 1991). "Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes". Circulation Research. 69 (2): 530–9. doi:10.1161/01.res.69.2.530. PMID 1860190.
  2. ↑ Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN (November 2000). "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9". American Journal of Human Genetics. 67 (5): 1121–8. doi:10.1016/S0002-9297(07)62942-5. PMC 1288554. PMID 11023810.
  3. ↑ Foth BJ, Goedecke MC, Soldati D (March 2006). "New insights into myosin evolution and classification". Proceedings of the National Academy of Sciences of the United States of America. 103 (10): 3681–6. doi:10.1073/pnas.0506307103. PMC 1533776. PMID 16505385.
  4. ↑ Odronitz F, Kollmar M (2007). "Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species". Genome Biology. 8 (9): R196. doi:10.1186/gb-2007-8-9-r196. PMC 2375034. PMID 17877792.
  5. ↑ Sebé-Pedrós A, Grau-Bové X, Richards TA, Ruiz-Trillo I (February 2014). "Evolution and classification of myosins, a paneukaryotic whole-genome approach". Genome Biology and Evolution. 6 (2): 290–305. doi:10.1093/gbe/evu013. PMC 3942036. PMID 24443438.
  6. ↑ 6.0 6.1 Dulyaninova NG, Bresnick AR (July 2013). "The heavy chain has its day: regulation of myosin-II assembly". Bioarchitecture. 3 (4): 77–85. doi:10.4161/bioa.26133. PMC 4201608. PMID 24002531.
  7. ↑ 7.0 7.1 Heissler SM, Manstein DJ (January 2013). "Nonmuscle myosin-2: mix and match". Cellular and Molecular Life Sciences. 70 (1): 1–21. doi:10.1007/s00018-012-1002-9. PMC 3535348. PMID 22565821.
  8. ↑ Heissler SM, Sellers JR (August 2016). "Kinetic Adaptations of Myosins for Their Diverse Cellular Functions". Traffic. 17 (8): 839–59. doi:10.1111/tra.12388. PMC 5067728. PMID 26929436.
  9. ↑ 9.0 9.1 Ma X, Adelstein RS (2014). "The role of vertebrate nonmuscle Myosin II in development and human disease". Bioarchitecture. 4 (3): 88–102. doi:10.4161/bioa.29766. PMC 4201603. PMID 25098841.
  10. ↑ 10.0 10.1 10.2 Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR (November 2009). "Non-muscle myosin II takes centre stage in cell adhesion and migration". Nature Reviews. Molecular Cell Biology. 10 (11): 778–90. doi:10.1038/nrm2786. PMC 2834236. PMID 19851336.
  11. ↑ D'Apolito M, Guarnieri V, Boncristiano M, Zelante L, Savoia A (March 2002). "Cloning of the murine non-muscle myosin heavy chain IIA gene ortholog of human MYH9 responsible for May-Hegglin, Sebastian, Fechtner, and Epstein syndromes". Gene. 286 (2): 215–22. PMID 11943476.
  12. ↑ 12.0 12.1 Eddinger TJ, Meer DP (August 2007). "Myosin II isoforms in smooth muscle: heterogeneity and function". American Journal of Physiology. Cell Physiology. 293 (2): C493–508. doi:10.1152/ajpcell.00131.2007. PMID 17475667.
  13. ↑ Sellers JR (March 2000). "Myosins: a diverse superfamily". Biochimica et Biophysica Acta. 1496 (1): 3–22. PMID 10722873.
  14. ↑ Burgess SA, Yu S, Walker ML, Hawkins RJ, Chalovich JM, Knight PJ (October 2007). "Structures of smooth muscle myosin and heavy meromyosin in the folded, shutdown state". Journal of Molecular Biology. 372 (5): 1165–78. doi:10.1016/j.jmb.2007.07.014. PMID 17707861.
  15. ↑ Jung HS, Komatsu S, Ikebe M, Craig R (August 2008). "Head-head and head-tail interaction: a general mechanism for switching off myosin II activity in cells". Molecular Biology of the Cell. 19 (8): 3234–42. doi:10.1091/mbc.E08-02-0206. PMC 2488288. PMID 18495867.
  16. ↑ Wendt T, Taylor D, Messier T, Trybus KM, Taylor KA (December 1999). "Visualization of head-head interactions in the inhibited state of smooth muscle myosin". The Journal of Cell Biology. 147 (7): 1385–90. PMC 2174251. PMID 10613897.
  17. ↑ Milton DL, Schneck AN, Ziech DA, Ba M, Facemyer KC, Halayko AJ, Baker JE, Gerthoffer WT, Cremo CR (January 2011). "Direct evidence for functional smooth muscle myosin II in the 10S self-inhibited monomeric conformation in airway smooth muscle cells". Proceedings of the National Academy of Sciences of the United States of America. 108 (4): 1421–6. doi:10.1073/pnas.1011784108. PMC 3029703. PMID 21205888.
  18. ↑ Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N (May 2005). "Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene". Cancer Research. 65 (9): 3772–80. doi:10.1158/0008-5472.CAN-04-4510. PMID 15867373.
  19. ↑ Li ZH, Bresnick AR (May 2006). "The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA". Cancer Research. 66 (10): 5173–80. doi:10.1158/0008-5472.CAN-05-3087. PMID 16707441.
  20. ↑ Dahan I, Petrov D, Cohen-Kfir E, Ravid S (January 2014). "The tumor suppressor Lgl1 forms discrete complexes with NMII-A and Par6α-aPKCζ that are affected by Lgl1 phosphorylation". Journal of Cell Science. 127 (Pt 2): 295–304. doi:10.1242/jcs.127357. PMID 24213535.
  21. ↑ Ravid S (2014). "The tumor suppressor Lgl1 regulates front-rear polarity of migrating cells". Cell Adhesion & Migration. 8 (4): 378–83. doi:10.4161/cam.29387. PMC 4594313. PMID 25482644.
  22. ↑ Hundt N, Steffen W, Pathan-Chhatbar S, Taft MH, Manstein DJ (February 2016). "Load-dependent modulation of non-muscle myosin-2A function by tropomyosin 4.2". Scientific Reports. 6: 20554. doi:10.1038/srep20554. PMC 4742800. PMID 26847712.
  23. ↑ Lin YH, Zhen YY, Chien KY, Lee IC, Lin WC, Chen MY, Pai LM (April 2017). "LIMCH1 regulates nonmuscle myosin-II activity and suppresses cell migration". Molecular Biology of the Cell. 28 (8): 1054–1065. doi:10.1091/mbc.E15-04-0218. PMC 5391182. PMID 28228547.
  24. ↑ Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS (October 2004). "Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice". The Journal of Biological Chemistry. 279 (40): 41263–6. doi:10.1074/jbc.C400352200. PMID 15292239.
  25. ↑ Wang A, Ma X, Conti MA, Liu C, Kawamoto S, Adelstein RS (August 2010). "Nonmuscle myosin II isoform and domain specificity during early mouse development". Proceedings of the National Academy of Sciences of the United States of America. 107 (33): 14645–50. doi:10.1073/pnas.1004023107. PMC 2930417. PMID 20679233.
  26. ↑ Zhang Y, Conti MA, Malide D, Dong F, Wang A, Shmist YA, Liu C, Zerfas P, Daniels MP, Chan CC, Kozin E, Kachar B, Kelley MJ, Kopp JB, Adelstein RS (January 2012). "Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A". Blood. 119 (1): 238–50. doi:10.1182/blood-2011-06-358853. PMC 3251230. PMID 21908426.
  27. ↑ Crish J, Conti MA, Sakai T, Adelstein RS, Egelhoff TT (October 2013). "Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality". Developmental Biology. 382 (1): 136–48. doi:10.1016/j.ydbio.2013.07.017. PMC 4186751. PMID 23911870.
  28. ↑ Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS (November 2010). "Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis". Molecular Biology of the Cell. 21 (22): 3952–62. doi:10.1091/mbc.E10-04-0293. PMC 2982113. PMID 20861308.
  29. ↑ Beach JR, Hammer JA (May 2015). "Myosin II isoform co-assembly and differential regulation in mammalian systems". Experimental Cell Research. 334 (1): 2–9. doi:10.1016/j.yexcr.2015.01.012. PMC 4433797. PMID 25655283.
  30. ↑ Beach JR, Shao L, Remmert K, Li D, Betzig E, Hammer JA (May 2014). "Nonmuscle myosin II isoforms coassemble in living cells". Current Biology. 24 (10): 1160–6. doi:10.1016/j.cub.2014.03.071. PMC 4108432. PMID 24814144.
  31. ↑ Shutova MS, Asokan SB, Talwar S, Assoian RK, Bear JE, Svitkina TM (September 2017). "Self-sorting of nonmuscle myosins IIA and IIB polarizes the cytoskeleton and modulates cell motility". The Journal of Cell Biology. 216 (9): 2877–2889. doi:10.1083/jcb.201705167. PMC 5584186. PMID 28701425.
  32. ↑ Kelley MJ, Jawien W, Ortel TL, Korczak JF (September 2000). "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly". Nature Genetics. 26 (1): 106–8. doi:10.1038/79069. PMID 10973260.
  33. ↑ Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, et al. (September 2000). "Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium". Nature Genetics. 26 (1): 103–5. doi:10.1038/79063. PMID 10973259.
  34. ↑ 34.0 34.1 34.2 34.3 Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, et al. (May 2003). "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. 82 (3): 203–15. doi:10.1097/01.md.0000076006.64510.5c. PMID 12792306.
  35. ↑ 35.0 35.1 35.2 35.3 Balduini CL, Pecci A, Savoia A (July 2011). "Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias". British Journal of Haematology. 154 (2): 161–74. doi:10.1111/j.1365-2141.2011.08716.x. PMID 21542825.
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 Pecci A, Klersy C, Gresele P, Lee KJ, De Rocco D, Bozzi V, et al. (February 2014). "MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations". Human Mutation. 35 (2): 236–47. doi:10.1002/humu.22476. PMID 24186861.
  37. ↑ 37.0 37.1 Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P, et al. (2012). "Alteration of liver enzymes is a feature of the MYH9-related disease syndrome". PLOS One. 7 (4): e35986. doi:10.1371/journal.pone.0035986. PMC 3338476. PMID 22558294.
  38. ↑ Savoia A, Pecci A (1993). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 20301740.
  39. ↑ 39.0 39.1 Noris P, Biino G, Pecci A, Civaschi E, Savoia A, Seri M, et al. (August 2014). "Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders". Blood. 124 (6): e4–e10. doi:10.1182/blood-2014-03-564328. PMC 4126341. PMID 24990887.
  40. ↑ Verver EJ, Topsakal V, Kunst HP, Huygen PL, Heller PG, Pujol-Moix N, et al. (January 2016). "Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease". Ear and Hearing. 37 (1): 112–20. doi:10.1097/AUD.0000000000000198. PMID 26226608.
  41. ↑ 41.0 41.1 Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, Inoue C, Kamiya T, Saito H (January 2003). "Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations". Laboratory Investigation; A Journal of Technical Methods and Pathology. 83 (1): 115–22. PMID 12533692.
  42. ↑ 42.0 42.1 Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, et al. (April 2010). "Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder". Thrombosis and Haemostasis. 103 (4): 826–32. doi:10.1160/TH09-08-0593. PMID 20174760.
  43. ↑ Kitamura K, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Furukawa K, et al. (November 2013). "Normal neutrophil myosin IIA localization in an immunofluorescence analysis can rule out MYH9 disorders". Journal of Thrombosis and Haemostasis. 11 (11): 2071–3. doi:10.1111/jth.12406. PMID 24106837.
  44. ↑ Greinacher A, Pecci A, Kunishima S, Althaus K, Nurden P, Balduini CL, Bakchoul T (July 2017). "Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders". Journal of Thrombosis and Haemostasis. 15 (7): 1511–1521. doi:10.1111/jth.13729. PMID 28457011.
  45. ↑ Saposnik B, Binard S, Fenneteau O, Nurden A, Nurden P, Hurtaud-Roux MF, Schlegel N (July 2014). "Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders". Molecular Genetics & Genomic Medicine. 2 (4): 297–312. doi:10.1002/mgg3.68. PMC 4113270. PMID 25077172.
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  47. ↑ Kunishima S, Takaki K, Ito Y, Saito H (April 2009). "Germinal mosaicism in MYH9 disorders: a family with two affected siblings of normal parents". British Journal of Haematology. 145 (2): 260–2. doi:10.1111/j.1365-2141.2009.07584.x. PMID 19208103.
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