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{{Infobox_gene}}
{{Infobox_gene}}
'''Myosin, heavy chain 9, non-muscle''' is a [[protein]] which in humans is encoded by the ''MYH9'' [[gene]].<ref name="pmid1860190">{{cite journal | vauthors = Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L | title = Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes | journal = Circulation Research | volume = 69 | issue = 2 | pages = 530–9 | date = August 1991 | pmid = 1860190 | doi = 10.1161/01.res.69.2.530 }}</ref><ref name="pmid11023810">{{cite journal | vauthors = Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN | title = Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9 | journal = American Journal of Human Genetics | volume = 67 | issue = 5 | pages = 1121–8 | date = November 2000 | pmid = 11023810 | pmc = 1288554 | doi = 10.1016/S0002-9297(07)62942-5 }}</ref>
'''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]].<ref name="pmid1860190">{{cite journal | vauthors = Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L | title = Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes | journal = Circulation Research | volume = 69 | issue = 2 | pages = 530–9 | date = August 1991 | pmid = 1860190 | doi = 10.1161/01.res.69.2.530 }}</ref><ref name="pmid11023810">{{cite journal | vauthors = Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN | title = Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9 | journal = American Journal of Human Genetics | volume = 67 | issue = 5 | pages = 1121–8 | date = November 2000 | pmid = 11023810 | pmc = 1288554 | doi = 10.1016/S0002-9297(07)62942-5 }}</ref>
 
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.<ref>{{cite journal | vauthors = Foth BJ, Goedecke MC, Soldati D | title = New insights into myosin evolution and classification | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 10 | pages = 3681–6 | date = March 2006 | pmid = 16505385 | pmc = 1533776 | doi = 10.1073/pnas.0506307103 }}</ref><ref>{{cite journal | vauthors = Odronitz F, Kollmar M | title = Drawing the tree of eukaryotic life based on the analysis of 2,269 manually annotated myosins from 328 species | journal = Genome Biology | volume = 8 | issue = 9 | pages = R196 | date = 2007 | pmid = 17877792 | pmc = 2375034 | doi = 10.1186/gb-2007-8-9-r196 }}</ref><ref>{{cite journal | vauthors = Sebé-Pedrós A, Grau-Bové X, Richards TA, Ruiz-Trillo I | title = Evolution and classification of myosins, a paneukaryotic whole-genome approach | journal = Genome Biology and Evolution | volume = 6 | issue = 2 | pages = 290–305 | date = February 2014 | pmid = 24443438 | pmc = 3942036 | doi = 10.1093/gbe/evu013 }}</ref> 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.<ref name="Dulyaninova_2013">{{cite journal | vauthors = Dulyaninova NG, Bresnick AR | title = The heavy chain has its day: regulation of myosin-II assembly | journal = Bioarchitecture | volume = 3 | issue = 4 | pages = 77–85 | date = July 2013 | pmid = 24002531 | pmc = 4201608 | doi = 10.4161/bioa.26133 }}</ref><ref name="Heissler_2013">{{cite journal | vauthors = Heissler SM, Manstein DJ | title = Nonmuscle myosin-2: mix and match | journal = Cellular and Molecular Life Sciences | volume = 70 | issue = 1 | pages = 1–21 | date = January 2013 | pmid = 22565821 | pmc = 3535348 | doi = 10.1007/s00018-012-1002-9 }}</ref><ref>{{cite journal | vauthors = Heissler SM, Sellers JR | title = Kinetic Adaptations of Myosins for Their Diverse Cellular Functions | journal = Traffic | volume = 17 | issue = 8 | pages = 839–59 | date = August 2016 | pmid = 26929436 | pmc = 5067728 | doi = 10.1111/tra.12388 }}</ref><ref name="Ma_2014">{{cite journal | vauthors = Ma X, Adelstein RS | title = The role of vertebrate nonmuscle Myosin II in development and human disease | journal = Bioarchitecture | volume = 4 | issue = 3 | pages = 88–102 | date = 2014 | pmid = 25098841 | pmc = 4201603 | doi = 10.4161/bioa.29766 }}</ref><ref name="Vicente-Manzanares_2009">{{cite journal | vauthors = Vicente-Manzanares M, Ma X, Adelstein RS, Horwitz AR | title = Non-muscle myosin II takes centre stage in cell adhesion and migration | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 11 | pages = 778–90 | date = November 2009 | pmid = 19851336 | pmc = 2834236 | doi = 10.1038/nrm2786 }}</ref>
 
== 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.<ref>{{cite journal | vauthors = D'Apolito M, Guarnieri V, Boncristiano M, Zelante L, Savoia A | title = Cloning of the murine non-muscle myosin heavy chain IIA gene ortholog of human MYH9 responsible for May-Hegglin, Sebastian, Fechtner, and Epstein syndromes | journal = Gene | volume = 286 | issue = 2 | pages = 215–22 | date = March 2002 | pmid = 11943476 }}</ref>
 
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.<ref name="Eddinger_2007">{{cite journal | vauthors = Eddinger TJ, Meer DP | title = Myosin II isoforms in smooth muscle: heterogeneity and function | journal = American Journal of Physiology. Cell Physiology | volume = 293 | issue = 2 | pages = C493-508 | date = August 2007 | pmid = 17475667 | doi = 10.1152/ajpcell.00131.2007 }}</ref> 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,<ref>{{cite journal | vauthors = Sellers JR | title = Myosins: a diverse superfamily | journal = Biochimica et Biophysica Acta | volume = 1496 | issue = 1 | pages = 3–22 | date = March 2000 | pmid = 10722873 }}</ref> 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.<ref name="Vicente-Manzanares_2009" /><ref name="Eddinger_2007" />
 
== 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 <ref name="Heissler_2013" /><ref name="Ma_2014" /><ref name="Vicente-Manzanares_2009" />). 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.<ref>{{cite journal | vauthors = Burgess SA, Yu S, Walker ML, Hawkins RJ, Chalovich JM, Knight PJ | title = Structures of smooth muscle myosin and heavy meromyosin in the folded, shutdown state | journal = Journal of Molecular Biology | volume = 372 | issue = 5 | pages = 1165–78 | date = October 2007 | pmid = 17707861 | doi = 10.1016/j.jmb.2007.07.014 }}</ref><ref>{{cite journal | vauthors = Jung HS, Komatsu S, Ikebe M, Craig R | title = Head-head and head-tail interaction: a general mechanism for switching off myosin II activity in cells | journal = Molecular Biology of the Cell | volume = 19 | issue = 8 | pages = 3234–42 | date = August 2008 | pmid = 18495867 | pmc = 2488288 | doi = 10.1091/mbc.E08-02-0206 }}</ref><ref>{{cite journal | vauthors = Wendt T, Taylor D, Messier T, Trybus KM, Taylor KA | title = Visualization of head-head interactions in the inhibited state of smooth muscle myosin | journal = The Journal of Cell Biology | volume = 147 | issue = 7 | pages = 1385–90 | date = December 1999 | pmid = 10613897 | pmc = 2174251 }}</ref><ref>{{cite journal | vauthors = Milton DL, Schneck AN, Ziech DA, Ba M, Facemyer KC, Halayko AJ, Baker JE, Gerthoffer WT, Cremo CR | title = Direct evidence for functional smooth muscle myosin II in the 10S self-inhibited monomeric conformation in airway smooth muscle cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 4 | pages = 1421–6 | date = January 2011 | pmid = 21205888 | pmc = 3029703 | doi = 10.1073/pnas.1011784108 }}</ref> 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.<ref name="Dulyaninova_2013" /> 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.<ref>{{cite journal | vauthors = Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N | title = Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene | journal = Cancer Research | volume = 65 | issue = 9 | pages = 3772–80 | date = May 2005 | pmid = 15867373 | doi = 10.1158/0008-5472.CAN-04-4510 }}</ref><ref>{{cite journal | vauthors = Li ZH, Bresnick AR | title = The S100A4 metastasis factor regulates cellular motility via a direct interaction with myosin-IIA | journal = Cancer Research | volume = 66 | issue = 10 | pages = 5173–80 | date = May 2006 | pmid = 16707441 | doi = 10.1158/0008-5472.CAN-05-3087 }}</ref> 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.<ref>{{cite journal | vauthors = Dahan I, Petrov D, Cohen-Kfir E, Ravid S | title = The tumor suppressor Lgl1 forms discrete complexes with NMII-A and Par6α-aPKCζ that are affected by Lgl1 phosphorylation | journal = Journal of Cell Science | volume = 127 | issue = Pt 2 | pages = 295–304 | date = January 2014 | pmid = 24213535 | doi = 10.1242/jcs.127357 }}</ref><ref>{{cite journal | vauthors = Ravid S | title = The tumor suppressor Lgl1 regulates front-rear polarity of migrating cells | journal = Cell Adhesion & Migration | volume = 8 | issue = 4 | pages = 378–83 | date = 2014 | pmid = 25482644 | pmc = 4594313 | doi = 10.4161/cam.29387 }}</ref> 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 <ref>{{cite journal | vauthors = Hundt N, Steffen W, Pathan-Chhatbar S, Taft MH, Manstein DJ | title = Load-dependent modulation of non-muscle myosin-2A function by tropomyosin 4.2 | journal = Scientific Reports | volume = 6 | pages = 20554 | date = February 2016 | pmid = 26847712 | pmc = 4742800 | doi = 10.1038/srep20554 }}</ref> and a novel actin stress fiber associated protein, LIM and calponin-homology domains1 (LIMCH1).<ref>{{cite journal | vauthors = Lin YH, Zhen YY, Chien KY, Lee IC, Lin WC, Chen MY, Pai LM | title = LIMCH1 regulates nonmuscle myosin-II activity and suppresses cell migration | journal = Molecular Biology of the Cell | volume = 28 | issue = 8 | pages = 1054–1065 | date = April 2017 | pmid = 28228547 | pmc = 5391182 | doi = 10.1091/mbc.E15-04-0218 }}</ref>
 
== 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.<ref>{{cite journal | vauthors = Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS | title = Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice | journal = The Journal of Biological Chemistry | volume = 279 | issue = 40 | pages = 41263–6 | date = October 2004 | pmid = 15292239 | doi = 10.1074/jbc.C400352200 }}</ref> 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.<ref>{{cite journal | vauthors = Wang A, Ma X, Conti MA, Liu C, Kawamoto S, Adelstein RS | title = Nonmuscle myosin II isoform and domain specificity during early mouse development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 33 | pages = 14645–50 | date = August 2010 | pmid = 20679233 | pmc = 2930417 | doi = 10.1073/pnas.1004023107 }}</ref> 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 <ref>{{cite journal | vauthors = 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 | title = Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A | journal = Blood | volume = 119 | issue = 1 | pages = 238–50 | date = January 2012 | pmid = 21908426 | pmc = 3251230 | doi = 10.1182/blood-2011-06-358853 }}</ref> 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.<ref>{{cite journal | vauthors = Crish J, Conti MA, Sakai T, Adelstein RS, Egelhoff TT | title = Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality | journal = Developmental Biology | volume = 382 | issue = 1 | pages = 136–48 | date = October 2013 | pmid = 23911870 | pmc = 4186751 | doi = 10.1016/j.ydbio.2013.07.017 }}</ref>
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 <ref>{{cite journal | vauthors = Ma X, Jana SS, Conti MA, Kawamoto S, Claycomb WC, Adelstein RS | title = Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis | journal = Molecular Biology of the Cell | volume = 21 | issue = 22 | pages = 3952–62 | date = November 2010 | pmid = 20861308 | pmc = 2982113 | doi = 10.1091/mbc.E10-04-0293 }}</ref> 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.<ref>{{cite journal | vauthors = Beach JR, Hammer JA | title = Myosin II isoform co-assembly and differential regulation in mammalian systems | journal = Experimental Cell Research | volume = 334 | issue = 1 | pages = 2–9 | date = May 2015 | pmid = 25655283 | pmc = 4433797 | doi = 10.1016/j.yexcr.2015.01.012 }}</ref><ref>{{cite journal | vauthors = Beach JR, Shao L, Remmert K, Li D, Betzig E, Hammer JA | title = Nonmuscle myosin II isoforms coassemble in living cells | journal = Current Biology | volume = 24 | issue = 10 | pages = 1160–6 | date = May 2014 | pmid = 24814144 | pmc = 4108432 | doi = 10.1016/j.cub.2014.03.071 }}</ref><ref>{{cite journal | vauthors = Shutova MS, Asokan SB, Talwar S, Assoian RK, Bear JE, Svitkina TM | title = Self-sorting of nonmuscle myosins IIA and IIB polarizes the cytoskeleton and modulates cell motility | journal = The Journal of Cell Biology | volume = 216 | issue = 9 | pages = 2877–2889 | date = September 2017 | pmid = 28701425 | pmc = 5584186 | doi = 10.1083/jcb.201705167 }}</ref>


==Clinical significance==
==Clinical significance==
MYH9 polymorphisms have been shown to associate with [[glomerulosclerosis]]<ref name="pmid18794856">{{cite journal | vauthors = Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA | title = MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis | journal = Nature Genetics | volume = 40 | issue = 10 | pages = 1175–84 | date = October 2008 | pmid = 18794856 | pmc = 2827354 | doi = 10.1038/ng.226 }}</ref> and non-diabetic [[chronic kidney disease|end stage renal disease]]<ref name="pmid18794854">{{cite journal | vauthors = Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS | title = MYH9 is associated with nondiabetic end-stage renal disease in African Americans | journal = Nature Genetics | volume = 40 | issue = 10 | pages = 1185–92 | date = October 2008 | pmid = 18794854 | pmc = 2614692 | doi = 10.1038/ng.232 | lastauthoramp = yes }}</ref> in African Americans and in Hispanic Americans,<ref>{{cite journal | vauthors = Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, Bercovici S, Kopp JB, Winkler CA, Nelson GW, Wasser WG, Skorecki K | title = African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans | journal = Human Molecular Genetics | volume = 19 | issue = 9 | pages = 1816–27 | date = May 2010 | pmid = 20144966 | pmc = 2850615 | doi = 10.1093/hmg/ddq040 }}</ref> though it was later shown that two independent variants in the nearby [[APOL1]] gene were responsible for the increased risk of disease.<ref>{{cite journal | vauthors = Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR | title = Association of trypanolytic ApoL1 variants with kidney disease in African Americans | journal = Science | volume = 329 | issue = 5993 | pages = 841–5 | date = August 2010 | pmid = 20647424 | pmc = 2980843 | doi = 10.1126/science.1193032 }}</ref><ref>{{cite journal | vauthors = Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K | title = Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene | journal = Human Genetics | volume = 128 | issue = 3 | pages = 345–50 | date = September 2010 | pmid = 20635188 | pmc = 2921485 | doi = 10.1007/s00439-010-0861-0 }}</ref>
'''''MYH9''-related disease.''' Mutations in ''MYH9'' cause a Mendelian autosomal-dominant disorder known as ''MYH9''-related disease (''MYH9''-RD).<ref>{{cite journal | vauthors = Kelley MJ, Jawien W, Ortel TL, Korczak JF | title = Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly | journal = Nature Genetics | volume = 26 | issue = 1 | pages = 106–8 | date = September 2000 | pmid = 10973260 | doi = 10.1038/79069 }}</ref><ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium | journal = Nature Genetics | volume = 26 | issue = 1 | pages = 103–5 | date = September 2000 | pmid = 10973259 | doi = 10.1038/79063 }}</ref><ref name="Seri_2003">{{cite journal | vauthors = Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A | display-authors = 6 | title = 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 | journal = Medicine | volume = 82 | issue = 3 | pages = 203–15 | date = May 2003 | pmid = 12792306 | doi = 10.1097/01.md.0000076006.64510.5c }}</ref><ref name="Balduini_2011">{{cite journal | vauthors = Balduini CL, Pecci A, Savoia A | title = Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias | journal = British Journal of Haematology | volume = 154 | issue = 2 | pages = 161–74 | date = July 2011 | pmid = 21542825 | doi = 10.1111/j.1365-2141.2011.08716.x }}</ref> 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.<ref name="Balduini_2011" /><ref name="Pecci_2014">{{cite journal | vauthors = Pecci A, Klersy C, Gresele P, Lee KJ, De Rocco D, Bozzi V, Russo G, Heller PG, Loffredo G, Ballmaier M, Fabris F, Beggiato E, Kahr WH, Pujol-Moix N, Platokouki H, Van Geet C, Noris P, Yerram P, Hermans C, Gerber B, Economou M, De Groot M, Zieger B, De Candia E, Fraticelli V, Kersseboom R, Piccoli GB, Zimmermann S, Fierro T, Glembotsky AC, Vianello F, Zaninetti C, Nicchia E, Güthner C, Baronci C, Seri M, Knight PJ, Balduini CL, Savoia A | display-authors = 6 | title = MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations | journal = Human Mutation | volume = 35 | issue = 2 | pages = 236–47 | date = February 2014 | pmid = 24186861 | doi = 10.1002/humu.22476 }}</ref><ref name="Pecci_2012">{{cite journal | vauthors = Pecci A, Biino G, Fierro T, Bozzi V, Mezzasoma A, Noris P, Ramenghi U, Loffredo G, Fabris F, Momi S, Magrini U, Pirastu M, Savoia A, Balduini C, Gresele P | display-authors = 6 | title = Alteration of liver enzymes is a feature of the MYH9-related disease syndrome | journal = PLOS One | volume = 7 | issue = 4 | pages = e35986 | date = 2012 | pmid = 22558294 | pmc = 3338476 | doi = 10.1371/journal.pone.0035986 }}</ref> 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.<ref name="Seri_2003" /> ''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.<ref>{{Cite book | url = https://www.ncbi.nlm.nih.gov/books/NBK2689/ |title=GeneReviews®|last=Savoia|first=Anna|last2=Pecci|first2=Alessandro|date=1993|publisher=University of Washington, Seattle|editor-last=Adam|editor-first=Margaret P.|location=Seattle (WA)|pmid=20301740|editor-last2=Ardinger|editor-first2=Holly H.|editor-last3=Pagon|editor-first3=Roberta A.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Bean|editor-first5=Lora JH|editor-last6=Stephens|editor-first6=Karen|editor-last7=Amemiya|editor-first7=Anne | name-list-format = vanc }}</ref>
 
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.<ref name="Balduini_2011" /><ref name="Pecci_2014" /> 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.<ref name="Seri_2003" /><ref name="Noris_2014">{{cite journal | vauthors = Noris P, Biino G, Pecci A, Civaschi E, Savoia A, Seri M, Melazzini F, Loffredo G, Russo G, Bozzi V, Notarangelo LD, Gresele P, Heller PG, Pujol-Moix N, Kunishima S, Cattaneo M, Bussel J, De Candia E, Cagioni C, Ramenghi U, Barozzi S, Fabris F, Balduini CL | display-authors = 6 | title = Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders | journal = Blood | volume = 124 | issue = 6 | pages = e4-e10 | date = August 2014 | pmid = 24990887 | pmc = 4126341 | doi = 10.1182/blood-2014-03-564328 }}</ref> 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".<ref name="Seri_2003" /><ref name="Balduini_2011" /> More than 50% of ''MYH9''-RD patients develop sensorineural hearing loss.<ref name="Pecci_2014" /> 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.<ref>{{cite journal | vauthors = Verver EJ, Topsakal V, Kunst HP, Huygen PL, Heller PG, Pujol-Moix N, Savoia A, Benazzo M, Fierro T, Grolman W, Gresele P, Pecci A | display-authors = 6 | title = Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease | journal = Ear and Hearing | volume = 37 | issue = 1 | pages = 112–20 | date = January 2016 | pmid = 26226608 | doi = 10.1097/AUD.0000000000000198 }}</ref> 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.<ref name="Pecci_2014" /> 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.<ref name="Pecci_2012" />
 
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.<ref name="Kunishima_2003">{{cite journal | vauthors = Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, Inoue C, Kamiya T, Saito H | title = Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 83 | issue = 1 | pages = 115–22 | date = January 2003 | pmid = 12533692 }}</ref><ref name="Savoia_2010">{{cite journal | vauthors = 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 | display-authors = 6 | title = Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder | journal = Thrombosis and Haemostasis | volume = 103 | issue = 4 | pages = 826–32 | date = April 2010 | pmid = 20174760 | doi = 10.1160/TH09-08-0593 }}</ref><ref>{{cite journal | vauthors = Kitamura K, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Furukawa K, Miyano S, Ogawa S, Kunishima S | display-authors = 6 | title = Normal neutrophil myosin IIA localization in an immunofluorescence analysis can rule out MYH9 disorders | journal = Journal of Thrombosis and Haemostasis | volume = 11 | issue = 11 | pages = 2071–3 | date = November 2013 | pmid = 24106837 | doi = 10.1111/jth.12406 }}</ref><ref>{{cite journal | vauthors = Greinacher A, Pecci A, Kunishima S, Althaus K, Nurden P, Balduini CL, Bakchoul T | title = Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders | journal = Journal of Thrombosis and Haemostasis | volume = 15 | issue = 7 | pages = 1511–1521 | date = July 2017 | pmid = 28457011 | doi = 10.1111/jth.13729 }}</ref>
 
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.<ref name="Pecci_2014" /><ref name="Kunishima_2003" /><ref>{{cite journal | vauthors = Saposnik B, Binard S, Fenneteau O, Nurden A, Nurden P, Hurtaud-Roux MF, Schlegel N | title = Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders | journal = Molecular Genetics & Genomic Medicine | volume = 2 | issue = 4 | pages = 297–312 | date = July 2014 | pmid = 25077172 | pmc = 4113270 | doi = 10.1002/mgg3.68 }}</ref> The disease is transmitted as an autosomal-dominant trait, however, about 35% of index cases are sporadic.<ref name="Savoia_2010" /> Sporadic forms mainly derive from ''de novo'' mutations; rare cases have been explained by germinal or somatic mosaicism.<ref>{{cite journal | vauthors = Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M, Saito H | title = First description of somatic mosaicism in MYH9 disorders | journal = British Journal of Haematology | volume = 128 | issue = 3 | pages = 360–5 | date = February 2005 | pmid = 15667538 | doi = 10.1111/j.1365-2141.2004.05323.x }}</ref><ref>{{cite journal | vauthors = Kunishima S, Takaki K, Ito Y, Saito H | title = Germinal mosaicism in MYH9 disorders: a family with two affected siblings of normal parents | journal = British Journal of Haematology | volume = 145 | issue = 2 | pages = 260–2 | date = April 2009 | pmid = 19208103 | doi = 10.1111/j.1365-2141.2009.07584.x }}</ref><ref>{{cite journal | vauthors = Kunishima S, Kitamura K, Matsumoto T, Sekine T, Saito H | title = Somatic mosaicism in MYH9 disorders: the need to carefully evaluate apparently healthy parents | journal = British Journal of Haematology | volume = 165 | issue = 6 | pages = 885–7 | date = June 2014 | pmid = 24611568 | doi = 10.1111/bjh.12797 }}</ref>
 
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.<ref name="Pecci_2014" /><ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease | journal = Human Mutation | volume = 29 | issue = 3 | pages = 409–17 | date = March 2008 | pmid = 18059020 | doi = 10.1002/humu.20661 }}</ref> Genotype-phenotype correlations have been reported also for the severity of thrombocytopenia, platelet size, and the features of leukocyte inclusions.<ref name="Pecci_2014" /><ref name="Noris_2014" /><ref>{{cite journal | vauthors = Kunishima S, Yoshinari M, Nishio H, Ida K, Miura T, Matsushita T, Hamaguchi M, Saito H | title = Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations | journal = European Journal of Haematology | volume = 78 | issue = 3 | pages = 220–6 | date = March 2007 | pmid = 17241369 | doi = 10.1111/j.1600-0609.2006.00806.x }}</ref>
 
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.<ref>{{cite journal | vauthors = Pecci A, Gresele P, Klersy C, Savoia A, Noris P, Fierro T, Bozzi V, Mezzasoma AM, Melazzini F, Balduini CL | title = Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations | journal = Blood | volume = 116 | issue = 26 | pages = 5832–7 | date = December 2010 | pmid = 20844233 | doi = 10.1182/blood-2010-08-304725 }}</ref> ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement.<ref>{{cite journal | vauthors = Pecci A, Granata A, Fiore CE, Balduini CL | title = Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome) | journal = Nephrology, Dialysis, Transplantation | volume = 23 | issue = 8 | pages = 2690–2 | date = August 2008 | pmid = 18503011 | doi = 10.1093/ndt/gfn277 }}</ref><ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease | journal = Kidney International | volume = 78 | issue = 2 | pages = 207–14 | date = July 2010 | pmid = 20200500 | doi = 10.1038/ki.2010.21 }}</ref> Cochlear implantation is effective in restoring hearing function in ''MYH9''-RD patients with severe/profound deafness.<ref>{{cite journal | vauthors = Pecci A, Verver EJ, Schlegel N, Canzi P, Boccio CM, Platokouki H, Krause E, Benazzo M, Topsakal V, Greinacher A | title = Cochlear implantation is safe and effective in patients with MYH9-related disease | journal = Orphanet Journal of Rare Diseases | volume = 9 | pages = 100 | date = June 2014 | pmid = 24980457 | pmc = 4105151 | doi = 10.1186/1750-1172-9-100 }}</ref>
 
'''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.<ref name="Schramek_2014">{{cite journal | vauthors = Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, Oristian D, Reva B, Fuchs E | title = Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas | journal = Science | volume = 343 | issue = 6168 | pages = 309–13 | date = January 2014 | pmid = 24436421 | pmc = 4159249 | doi = 10.1126/science.1248627 }}</ref> In another mouse model, ablation of ''Myh9'' in the tongue epithelium led to the development of tongue SCC.<ref>{{cite journal | vauthors = Conti MA, Saleh AD, Brinster LR, Cheng H, Chen Z, Cornelius S, Liu C, Ma X, Van Waes C, Adelstein RS | title = Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma | journal = Scientific Reports | volume = 5 | pages = 14068 | date = September 2015 | pmid = 26369831 | pmc = 4572924 | doi = 10.1038/srep14068 }}</ref> 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.<ref name="Kas_2017">{{cite journal | vauthors = Kas SM, de Ruiter JR, Schipper K, Annunziato S, Schut E, Klarenbeek S, Drenth AP, van der Burg E, Klijn C, Ten Hoeve JJ, Adams DJ, Koudijs MJ, Wesseling J, Nethe M, Wessels LF, Jonkers J | title = Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma | journal = Nature Genetics | volume = 49 | issue = 8 | pages = 1219–1230 | date = August 2017 | pmid = 28650484 | doi = 10.1038/ng.3905 }}</ref> 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.<ref name="Schramek_2014" /><ref name="Kas_2017" />
 
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]]<ref name="pmid18794856">{{cite journal | vauthors = Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA | title = MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis | journal = Nature Genetics | volume = 40 | issue = 10 | pages = 1175–84 | date = October 2008 | pmid = 18794856 | pmc = 2827354 | doi = 10.1038/ng.226 }}</ref> and non-diabetic [[chronic kidney disease|end stage renal disease]]<ref name="pmid18794854">{{cite journal | vauthors = Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS | display-authors = 6 | title = MYH9 is associated with nondiabetic end-stage renal disease in African Americans | journal = Nature Genetics | volume = 40 | issue = 10 | pages = 1185–92 | date = October 2008 | pmid = 18794854 | pmc = 2614692 | doi = 10.1038/ng.232 }}</ref> in African Americans and in Hispanic Americans.<ref>{{cite journal | vauthors = Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, Bercovici S, Kopp JB, Winkler CA, Nelson GW, Wasser WG, Skorecki K | display-authors = 6 | title = African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans | journal = Human Molecular Genetics | volume = 19 | issue = 9 | pages = 1816–27 | date = May 2010 | pmid = 20144966 | pmc = 2850615 | doi = 10.1093/hmg/ddq040 }}</ref> 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.<ref>{{cite journal | vauthors = Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR | display-authors = 6 | title = Association of trypanolytic ApoL1 variants with kidney disease in African Americans | journal = Science | volume = 329 | issue = 5993 | pages = 841–5 | date = August 2010 | pmid = 20647424 | pmc = 2980843 | doi = 10.1126/science.1193032 }}</ref><ref>{{cite journal | vauthors = Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K | display-authors = 6 | title = Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene | journal = Human Genetics | volume = 128 | issue = 3 | pages = 345–50 | date = September 2010 | pmid = 20635188 | pmc = 2921485 | doi = 10.1007/s00439-010-0861-0 }}</ref><ref>{{cite journal | vauthors = Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA | title = APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 11 | pages = 2129–37 | date = November 2011 | pmid = 21997394 | pmc = 3231787 | doi = 10.1681/ASN.2011040388 }}</ref> 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.<ref>{{cite journal | vauthors = Cooke JN, Bostrom MA, Hicks PJ, Ng MC, Hellwege JN, Comeau ME, Divers J, Langefeld CD, Freedman BI, Bowden DW | title = Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans | journal = Nephrology, Dialysis, Transplantation | volume = 27 | issue = 4 | pages = 1505–11 | date = April 2012 | pmid = 21968013 | pmc = 3315672 | doi = 10.1093/ndt/gfr522 }}</ref><ref>{{cite journal | vauthors = Cheng W, Zhou X, Zhu L, Shi S, Lv J, Liu L, Zhang H | title = Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese | journal = Nephrology, Dialysis, Transplantation | volume = 26 | issue = 8 | pages = 2544–9 | date = August 2011 | pmid = 21245129 | doi = 10.1093/ndt/gfq768 }}</ref><ref>{{cite journal | vauthors = O'Seaghdha CM, Parekh RS, Hwang SJ, Li M, Köttgen A, Coresh J, Yang Q, Fox CS, Kao WH | title = The MYH9/APOL1 region and chronic kidney disease in European-Americans | journal = Human Molecular Genetics | volume = 20 | issue = 12 | pages = 2450–6 | date = June 2011 | pmid = 21429915 | pmc = 3098737 | doi = 10.1093/hmg/ddr118 }}</ref>
 
Inherited ''MYH9'' mutations may be responsible for non-syndromic hearing loss.<ref>{{cite journal | vauthors = Wu CC, Lin YH, Lu YC, Chen PJ, Yang WS, Hsu CJ, Chen PL | title = Application of massively parallel sequencing to genetic diagnosis in multiplex families with idiopathic sensorineural hearing impairment | journal = PLOS One | volume = 8 | issue = 2 | pages = e57369 | date = 2013 | pmid = 23451214 | pmc = 3579845 | doi = 10.1371/journal.pone.0057369 }}</ref><ref>{{cite journal | vauthors = Kim SJ, Lee S, Park HJ, Kang TH, Sagong B, Baek JI, Oh SK, Choi JY, Lee KY, Kim UK | title = Genetic association of MYH genes with hereditary hearing loss in Korea | journal = Gene | volume = 591 | issue = 1 | pages = 177–82 | date = October 2016 | pmid = 27393652 | doi = 10.1016/j.gene.2016.07.011 }}</ref><ref>{{cite journal | vauthors = Miyagawa M, Naito T, Nishio SY, Kamatani N, Usami S | title = Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients | journal = PLOS One | volume = 8 | issue = 8 | pages = e71381 | date = 2013 | pmid = 23967202 | pmc = 3742761 | doi = 10.1371/journal.pone.0071381 }}</ref>


== Model organisms ==
== Other model organisms ==


{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
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| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBCS/citrobacter-challenge/ |title=''Citrobacter'' infection data for Myh9 |publisher=Wellcome Trust Sanger Institute}}</ref>
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBCS/citrobacter-challenge/ |title=''Citrobacter'' infection data for Myh9 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | author = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages =  925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | vauthors = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages =  925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
|}
[[Model organism]]s have been used in the study of MYH9 function. A conditional [[knockout mouse]] line, called ''Myh9<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Myh9 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4432815 |title=Mouse Genome Informatics}}</ref> 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.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
[[Model organism]]s have been used in the study of MYH9 function. A conditional [[knockout mouse]] line, called ''Myh9<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Myh9 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4432815 |title=Mouse Genome Informatics}}</ref> 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.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
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Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | date = June 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty six tests were carried out on [[mutant]] mice and two significant abnormalities were observed.<ref name="mgp_reference" />  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.<ref name="mgp_reference" />
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | date = June 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref> Twenty six tests were carried out on [[mutant]] mice and two significant abnormalities were observed.<ref name="mgp_reference" />  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.<ref name="mgp_reference" />


== Interactions ==
== Other interactions ==


MYH9 has been shown to [[Protein-protein interaction|interact]] with [[PRKCE]].<ref name=pmid11897493>{{cite journal | vauthors = England K, Ashford D, Kidd D, Rumsby M | title = PKC epsilon is associated with myosin IIA and actin in fibroblasts | journal = Cellular Signalling | volume = 14 | issue = 6 | pages = 529–36 | date = June 2002 | pmid = 11897493 | doi = 10.1016/S0898-6568(01)00277-7 }}</ref>
MYH9 has been shown to [[Protein-protein interaction|interact]] with [[PRKCE]].<ref name=pmid11897493>{{cite journal | vauthors = England K, Ashford D, Kidd D, Rumsby M | title = PKC epsilon is associated with myosin IIA and actin in fibroblasts | journal = Cellular Signalling | volume = 14 | issue = 6 | pages = 529–36 | date = June 2002 | pmid = 11897493 | doi = 10.1016/S0898-6568(01)00277-7 }}</ref>
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== References ==
== References ==
{{Reflist|33em}}
{{Reflist|32em}}


== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|32em}}
* {{cite journal | vauthors = Starr R, Offer G | title = The interaction of C-protein with heavy meromyosin and subfragment-2 | journal = The Biochemical Journal | volume = 171 | issue = 3 | pages = 813–6 | date = June 1978 | pmid = 352343 | pmc = 1184031 | doi =  }}
* {{cite journal | vauthors = Starr R, Offer G | title = The interaction of C-protein with heavy meromyosin and subfragment-2 | journal = The Biochemical Journal | volume = 171 | issue = 3 | pages = 813–6 | date = June 1978 | pmid = 352343 | pmc = 1184031 | doi =  }}
* {{cite journal | vauthors = Lee CL, Atassi MZ | title = Enzymic and immunochemical properties of lysozyme. Accurate definition of the antigenic site around the disulphide bridge 30-115 (site 3) by 'surface-simulation' synthesis | journal = The Biochemical Journal | volume = 167 | issue = 3 | pages = 571–81 | date = December 1977 | pmid = 603622 | pmc = 1183703 | doi =  }}
* {{cite journal | vauthors = Lee CL, Atassi MZ | title = Enzymic and immunochemical properties of lysozyme. Accurate definition of the antigenic site around the disulphide bridge 30-115 (site 3) by 'surface-simulation' synthesis | journal = The Biochemical Journal | volume = 167 | issue = 3 | pages = 571–81 | date = December 1977 | pmid = 603622 | pmc = 1183703 | doi =  10.1042/bj1670571}}
* {{cite journal | vauthors = Tweed WA, Phua WT, Chong KY, Lim E, Lee TL | title = Large tidal volume ventilation improves pulmonary gas exchange during lower abdominal surgery in Trendelenburg's position | journal = Canadian Journal of Anaesthesia = Journal Canadien d'Anesthesie | volume = 38 | issue = 8 | pages = 989–95 | date = November 1991 | pmid = 1752022 | doi = 10.1007/BF03008617 }}
* {{cite journal | vauthors = Tweed WA, Phua WT, Chong KY, Lim E, Lee TL | title = Large tidal volume ventilation improves pulmonary gas exchange during lower abdominal surgery in Trendelenburg's position | journal = Canadian Journal of Anaesthesia = Journal Canadien d'Anesthesie | volume = 38 | issue = 8 | pages = 989–95 | date = November 1991 | pmid = 1752022 | doi = 10.1007/BF03008617 }}
* {{cite journal | vauthors = Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L | title = Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes | journal = Circulation Research | volume = 69 | issue = 2 | pages = 530–9 | date = August 1991 | pmid = 1860190 | doi = 10.1161/01.res.69.2.530 }}
* {{cite journal | vauthors = Simons M, Wang M, McBride OW, Kawamoto S, Yamakawa K, Gdula D, Adelstein RS, Weir L | title = Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes | journal = Circulation Research | volume = 69 | issue = 2 | pages = 530–9 | date = August 1991 | pmid = 1860190 | doi = 10.1161/01.res.69.2.530 }}
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* {{cite journal | vauthors = Moos C, Feng IN | title = Effect of C-protein on actomyosin ATPase | journal = Biochimica et Biophysica Acta | volume = 632 | issue = 2 | pages = 141–9 | date = October 1980 | pmid = 6448079 | doi = 10.1016/0304-4165(80)90071-9 }}
* {{cite journal | vauthors = Moos C, Feng IN | title = Effect of C-protein on actomyosin ATPase | journal = Biochimica et Biophysica Acta | volume = 632 | issue = 2 | pages = 141–9 | date = October 1980 | pmid = 6448079 | doi = 10.1016/0304-4165(80)90071-9 }}
* {{cite journal | vauthors = Obermann WM, Plessmann U, Weber K, Fürst DO | title = Purification and biochemical characterization of myomesin, a myosin-binding and titin-binding protein, from bovine skeletal muscle | journal = European Journal of Biochemistry | volume = 233 | issue = 1 | pages = 110–5 | date = October 1995 | pmid = 7588733 | doi = 10.1111/j.1432-1033.1995.110_1.x }}
* {{cite journal | vauthors = Obermann WM, Plessmann U, Weber K, Fürst DO | title = Purification and biochemical characterization of myomesin, a myosin-binding and titin-binding protein, from bovine skeletal muscle | journal = European Journal of Biochemistry | volume = 233 | issue = 1 | pages = 110–5 | date = October 1995 | pmid = 7588733 | doi = 10.1111/j.1432-1033.1995.110_1.x }}
* {{cite journal | vauthors = Maupin P, Phillips CL, Adelstein RS, Pollard TD | title = Differential localization of myosin-II isozymes in human cultured cells and blood cells | journal = Journal of Cell Science | volume = 107 ( Pt 11) | issue = 11 | pages = 3077–90 | date = November 1994 | pmid = 7699007 | doi =  }}
* {{cite journal | vauthors = Maupin P, Phillips CL, Adelstein RS, Pollard TD | title = Differential localization of myosin-II isozymes in human cultured cells and blood cells | journal = Journal of Cell Science | volume = 107 | issue = 11 | pages = 3077–90 | date = November 1994 | pmid = 7699007 | doi =  }}
* {{cite journal | vauthors = Bement WM, Hasson T, Wirth JA, Cheney RE, Mooseker MS | title = Identification and overlapping expression of multiple unconventional myosin genes in vertebrate cell types | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 14 | pages = 6549–53 | date = July 1994 | pmid = 8022818 | pmc = 44240 | doi = 10.1073/pnas.91.14.6549 }}
* {{cite journal | vauthors = Bement WM, Hasson T, Wirth JA, Cheney RE, Mooseker MS | title = Identification and overlapping expression of multiple unconventional myosin genes in vertebrate cell types | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 14 | pages = 6549–53 | date = July 1994 | pmid = 8022818 | pmc = 44240 | doi = 10.1073/pnas.91.14.6549 }}
* {{cite journal | vauthors = Eilertsen KJ, Kazmierski ST, Keller TC | title = Cellular titin localization in stress fibers and interaction with myosin II filaments in vitro | journal = The Journal of Cell Biology | volume = 126 | issue = 5 | pages = 1201–10 | date = September 1994 | pmid = 8063857 | pmc = 2120159 | doi = 10.1083/jcb.126.5.1201 }}
* {{cite journal | vauthors = Eilertsen KJ, Kazmierski ST, Keller TC | title = Cellular titin localization in stress fibers and interaction with myosin II filaments in vitro | journal = The Journal of Cell Biology | volume = 126 | issue = 5 | pages = 1201–10 | date = September 1994 | pmid = 8063857 | pmc = 2120159 | doi = 10.1083/jcb.126.5.1201 }}
* {{cite journal | vauthors = Shoeman RL, Sachse C, Höner B, Mothes E, Kaufmann M, Traub P | title = Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin | journal = The American Journal of Pathology | volume = 142 | issue = 1 | pages = 221–30 | date = January 1993 | pmid = 8424456 | pmc = 1886840 | doi =  }}
* {{cite journal | vauthors = Shoeman RL, Sachse C, Höner B, Mothes E, Kaufmann M, Traub P | title = Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin | journal = The American Journal of Pathology | volume = 142 | issue = 1 | pages = 221–30 | date = January 1993 | pmid = 8424456 | pmc = 1886840 | doi =  }}
* {{cite journal | vauthors = Lalwani AK, Linthicum FH, Wilcox ER, Moore JK, Walters FC, San Agustin TB, Mislinski J, Miller MR, Sinninger Y, Attaie A, Luxford WM | title = A five-generation family with late-onset progressive hereditary hearing impairment due to cochleosaccular degeneration | journal = Audiology & Neuro-Otology | volume = 2 | issue = 3 | pages = 139–54 | year = 1998 | pmid = 9390828 | doi = 10.1159/000259237 }}
* {{cite journal | vauthors = Lalwani AK, Linthicum FH, Wilcox ER, Moore JK, Walters FC, San Agustin TB, Mislinski J, Miller MR, Sinninger Y, Attaie A, Luxford WM | title = A five-generation family with late-onset progressive hereditary hearing impairment due to cochleosaccular degeneration | journal = Audiology and Neuro-Otology | volume = 2 | issue = 3 | pages = 139–54 | year = 1998 | pmid = 9390828 | doi = 10.1159/000259237 }}
* {{cite journal | vauthors = Ford HL, Silver DL, Kachar B, Sellers JR, Zain SB | title = Effect of Mts1 on the structure and activity of nonmuscle myosin II | journal = Biochemistry | volume = 36 | issue = 51 | pages = 16321–7 | date = December 1997 | pmid = 9405067 | doi = 10.1021/bi971182l }}
* {{cite journal | vauthors = Ford HL, Silver DL, Kachar B, Sellers JR, Zain SB | title = Effect of Mts1 on the structure and activity of nonmuscle myosin II | journal = Biochemistry | volume = 36 | issue = 51 | pages = 16321–7 | date = December 1997 | pmid = 9405067 | doi = 10.1021/bi971182l }}
* {{cite journal | vauthors = Obermann WM, van der Ven PF, Steiner F, Weber K, Fürst DO | title = Mapping of a myosin-binding domain and a regulatory phosphorylation site in M-protein, a structural protein of the sarcomeric M band | journal = Molecular Biology of the Cell | volume = 9 | issue = 4 | pages = 829–40 | date = April 1998 | pmid = 9529381 | pmc = 25310 | doi = 10.1091/mbc.9.4.829 }}
* {{cite journal | vauthors = Obermann WM, van der Ven PF, Steiner F, Weber K, Fürst DO | title = Mapping of a myosin-binding domain and a regulatory phosphorylation site in M-protein, a structural protein of the sarcomeric M band | journal = Molecular Biology of the Cell | volume = 9 | issue = 4 | pages = 829–40 | date = April 1998 | pmid = 9529381 | pmc = 25310 | doi = 10.1091/mbc.9.4.829 }}
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{{Cytoskeletal Proteins}}
{{Cytoskeletal Proteins}}
{{NLM content}}
{{NLM content}}


[[Category:Genes mutated in mice]]
[[Category:Genes mutated in mice]]

Revision as of 08:00, 27 July 2018

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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.
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  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.
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  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.
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  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.
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