Abstract
The MYH9 gene encodes the heavy chain (MHCII) of non-muscle myosin II A (NMII-A). This is an actin-binding molecular motor essential for development that participates in many crucial cellular processes such as adhesion, cell migration, cytokinesis and polarization, maintenance of cell shape and signal transduction. Several types of mutations in the MYH9 gene cause an array of autosomal dominant disorders, globally known as MYH9-related diseases (MYH9-RD). These include May-Hegglin anomaly (MHA), Epstein syndrome (EPS), Fechtner syndrome (FTS) and Sebastian platelet syndrome (SPS). Although caused by different MYH9 mutations, all patients present macrothrombocytopenia, but may later display other pathologies, including loss of hearing, renal failure and presenile cataracts. The correlation between the molecular and cellular effects of the different mutations and clinical presentation are beginning to be established. In this review, we correlate the defects that MYH9 mutations cause at a molecular and cellular level (for example, deficient filament formation, altered ATPase activity or actin-binding) with the clinical presentation of the syndromes in human patients. We address why these syndromes are tissue restricted, and the existence of possible compensatory mechanisms, including residual activity of mutant NMII-A and/or the formation of heteropolymers or co-polymers with other NMII isoforms.
Highlights
Myosins constitute a large superfamily of proteins that convert the energy produced duringATP hydrolysis into a conformational change that propels molecular motion
Some mutants are functional enough to enable a “close to normal” non-muscle myosin II A (NMII-A) function in cellular terms; this includes the possibility of finding mutant/wild-type assemblies that work to wild-type filaments as a whole; ii) different mutations cause various degrees of protein aggregation over time, with deleterious consequences that would largely depend on the dynamics of aggregation; iii) non-muscle myosin II (NMII)-A, either wild-type or mutant, can copolymerize with other myosins, if expressed in the cell/tissue under analysis
We have shown that the cellular phenotype caused by the shRNA-based depletion of NMII-A in fibroblasts is dose dependent, that is, the severity of the cellular phenotype is proportional to the degree of deletion, and cells displaying moderate decreases of NMII-A have relatively normal phenotypes
Summary
Myosins constitute a large superfamily of proteins that convert the energy produced during. Reason why these disorders, which are catalogued as rare diseases, may be more prevalent than the wealth of clinical and genetic data, few attempts have been made to explain the phenotype of prevalence is established at approximately. Of the MYH9 wealth of clinical and genetic data, few attempts have been made to explain the phenotype of these product, MHCII-A, and its functional unit, NMII-A (see Section 2 for an explanation on nomenclature). Patients based on the well-characterized cellular and molecular function of the MYH9 gene product, This review intends to describe the current state of the art regarding the correlation between genotype. This and molecular phenotype from pointstate of view cell biologist, trying to fillgenotype this gap.and review intends to describe thethe current of theof artaregarding the correlation between molecular phenotype from the point of view of a cell biologist, trying to fill this gap
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