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.

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 [11][13][14]).

All NM IIs have two important features: they are MgATPase enzymes that can hydrolyze ATP thereby converting chemical energy into mechanical movement.

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.

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 tumor suppressor protein Lgl1 also inhibits the ability of NM IIA to assemble into filaments in vitro.

[24][25] In addition, it regulates the cellular localization of NM IIA and contributes to the maturation of focal adhesions.

Absence of NM IIA results in a compact and underdeveloped labyrinthine layer in the placenta which lacks fetal blood vessel invasion.

[36][37][38][39] 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.

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.

The actual prevalence is expected to be higher, as mild forms are often discovered incidentally and patients are frequently misdiagnosed with other disorders.

[45][46][47][48] 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.

[46] Sporadic forms mainly derive from de novo mutations; rare cases have been explained by germinal or somatic mosaicism.

[40][43][54] 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.

[55] ACE-inhibitors or angiotensin II receptor blockers may be effective in reducing proteinuria when given at the early stage of kidney involvement.