Disease relevance of MYO9A

• From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30 [1].
• A statistically significant increase in cell size, [3H]leucine incorporation, and expression of well-characterized markers of cardiac hypertrophy, namely cardiac alpha-actin and myosin light chain, were observed in response to leptin [2].
• Shifted cells undergo a process of cell hypertrophy, as demonstrated by increased time of flight and forward scatter, as well as increased expression of the contractile proteins alpha-smooth muscle actin, myosin light chain kinase, and SM22 [3].
• As mutations in the gene encoding NINAC, a Drosophila melanogaster class III myosin, cause retinal degeneration, human homologs of this gene are potential candidates for human retinal disease [4].
• Quantification and characterization of myosin peptide-specific CD4+ T cells in autoimmune myocarditis [5].

Psychiatry related information on MYO9A

• The segment of smooth muscle regulatory light chain essential for the phosphorylation dependent activation of actomyosin motor activity and the binding of myosin heavy chain was identified [6].
• Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development [7].
• After exercise, the recovery of phosphocreatine-an index of oxidative metabolic capacity of the muscle-was slower in the beta myosin heavy chain group (mean half time 0.65 (0.08) minutes) than in the troponin T group (0.60 (0.17) minutes) or controls (0.48 (0.14) minutes) [8].
• In hyperthyroidism, the cross-bridge movement significantly preceded tension development, suggesting that hyperthyroid myosin (V1) has a longer latency period between the shift to the vicinity of the thin filament and force development [9].
• Newly-reported structural information about certain proximities between points on bound nucleotide and points on the heavy chain of myosin S-1 are incorporated into a previously-reported [Botts, J. Thomason, J.F. & Morales, M.F. Proc. Nat. Acad. Sci. USA, 86, 2204-2208 (1989)] structure of S-1 [10].

High impact information on MYO9A

• Kinetics shows that the binding of myosin to actin is a two-step process which affects ATP and ADP affinity [11].
• Molecular genetics of myosin [12].
• Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament determines the interaction of myosin with the binding sites on actin [13].
• 3) The initial rate of force development depends mostly on the extent of Ca(2+) activation of the thin filament and myosin kinetic properties but depends little on the initial force level [13].
• Second, the technology to measure picoNewton forces and nanometer distances has provided direct determinations of the force and step length generated by a single myosin molecule interacting with a single actin filament [14].

Chemical compound and disease context of MYO9A

• Compounds interfering with actin function, including phalloidin, the catalytic subunit of Clostridium botulinum C2 toxin, and N-ethylmaleimide-treated myosin S1 fragments were microinjected into the axon [15].
• The presence of ventricular myosin light chains in the atria of children with congenital heart disease was demonstrated by two-dimensional polyacrylamide gel electrophoresis, peptide mapping, and Western blot analysis [16].
• All Lewis rats immunized with the rod exhibited severe myocarditis, and the immunization of the cyanogen bromide-cleaved peptide equivalent to human beta-cardiac myosin heavy chain RDCB9 (residues 1070 to 1165) induced moderate myocarditis [17].
• Treatment of ovarian cancer cells with alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which are essential processes for cell migration [18].
• Because streptococcal M proteins produced valvular heart disease in Lewis rats and have been linked to anti-cardiac myosin responses, we reacted myosin-sensitized lymphocytes isolated from the hearts of Lewis rats with peptides of streptococcal M5 protein in tritiated thymidine assays [19].

Biological context of MYO9A

• The Ku protein complex interacts with YY1, is up-regulated in human heart failure, and represses alpha myosin heavy-chain gene expression [20].
• Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other [21].
• Actin-based propulsion is driven by the free energy released by ATP hydrolysis linked to actin polymerization, and does not require myosin [22].
• Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain [23].
• To assess whether this phenotype was specific for the FHC mutants and not generalizable to any myosin mutation, COS cells were transfected with a construct encoding an MHC with a 168-amino acid deletion of the hinge/rod region [24].

Anatomical context of MYO9A

• Human aortic SMCs grown on polymerized collagen showed high expression levels of contractile markers (smooth muscle alpha-actin, myosin heavy chain, and calponin) [25].
• This is accompanied by a coordinated increase in synthesis of other contractile proteins and, in skeletal muscle only, by isoform shifts of myosin light chains and of the TM-TN regulatory system [26].
• In hair cells of the inner ear, evidence suggests that an extracellular tip link pulls on a channel, which attached intracellularly to actin via a tension-regulating myosin 1beta [27].
• Wild-type alpha MHC transfected into COS cells forms structures previously shown to be arrays of thick filaments, which also resemble myosin structures observed early in differentiation of muscle cells [24].
• Accumulation of mRNAs encoding alpha-skeletal, alpha-cardiac, beta- and gamma-actin, total myosin heavy chain, and alpha- and beta-tubulin also displayed discordant regulation, which has important implications for sarcomere assembly [28].

Associations of MYO9A with chemical compounds

• As the differentiation in a culture progressed, 1,10-phenanthroline became less effective in blocking the accumulation of creatine kinase and myosin heavy chain [29].
• These proteins include the following: integrin alpha-4, myosin heavy chain (nonmuscle type A), myosin light-chain alkali (nonmuscle isoform), and beta-actin [30].
• Myocyte-specific enhancer factor 2 and thyroid hormone receptor associate and synergistically activate the alpha-cardiac myosin heavy-chain gene [31].
• The expression of the dominant negative Cdc42 mutant inhibited contractile force and the increase in actin polymerization in response to acetylcholine stimulation but did not inhibit the increase in myosin light chain phosphorylation [32].
• Ca(2+)-dependent calmodulin/myosin light-chain kinase-mediated contraction was examined by direct Ca(2+) (pCa8-5) stimulation to beta-escin permeabilized aortic strips; the pCa-force curve in Pkd2(+/-) strips was not shifted, thereby indicating that PE induced dosage-response alteration that resulted from Ca(2+)-independent mechanisms [33].

Analytical, diagnostic and therapeutic context of MYO9A

• Advances in our knowledge of the regulation of cardiac myosin isoforms made possible by molecular cloning of the alpha- and beta-MHCs genes are reviewed [34].
• Redifferentiation of smooth muscle cells after coronary angioplasty determined via myosin heavy chain expression [35].
• The presence of differentiated human muscle fibers was assessed by quantitative PCR measurement of the human alpha-actin mRNA together with immunohistochemical staining using specific antibodies for spectrin and the slow adult myosin heavy chain [36].
• As shown by in situ hybridization with cloned probes and analysis of in vitro translation products, M. occulta embryos do not accumulate high levels of alpha actin or myosin heavy chain mRNA [37].
• Concomitantly, addition of BMP-7 stimulates the expression of SMC-specific markers, namely alpha-actin and heavy chain myosin as examined by RT-PCR and Northern blot analyses [38].

References