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MYH9

Official Full Name
myosin, heavy chain 9, non-muscle
Background
This gene encodes a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain. The protein is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in MYH9 are the cause of non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness.
Synonyms
MYH9; myosin, heavy chain 9, non-muscle; DFNA17, myosin, heavy polypeptide 9, non muscle; myosin-9; EPSTS; FTNS; MHA; NMHC II A; NMMHCA; nonmuscle myosin heavy chain II A; myosin heavy chain 9; non-muscle myosin heavy chain A; non-muscle myosin heavy cha; non-muscle myosin heavy chain IIa; nonmuscle myosin heavy chain II-A; myosin heavy chain, non-muscle IIa; cellular myosin heavy chain, type A; non-muscle myosin heavy polypeptide 9; BDPLT6; DFNA17; NMHC-II-A; NMMHC-IIA; MGC104539; NMMHC; myosin; nonmuscle; non-muscle; type A; NMMHC-A; NMMHC II-a; non-muscle IIa; heavy polypeptide 9; myosin heavy chain, nonmuscle; non

The MYH9 gene is located at 22q12.3-13.1 and has a full length of 139 kb. It has 40 exons encoding a nonmuscle myosin heavy chain IIA (NMMHC2 IIA) with a relative molecular mass of approximately 224,000. This protein is an important component of the non-muscle cytoskeleton and is involved in cell movement. The human non-muscle actin heavy chain (NMMHC) has three types: A, B, and C. Most cells express these three heavy chains, encoding protein non-muscle myosin heavy chain II, type A and subtypes in eukaryotic cells.

Potential mechanisms of expression regulation of Pax5 gene mediated by the Thy28-MYH9 complex. Figure 1. Potential mechanisms of expression regulation of Pax5 gene mediated by the Thy28-MYH9 complex. (Fujita, T., et al. 2015)

The MYH9 gene is involved in the encoding of a nonmuscle myosin heavy chain A (NMMHCA) polypeptide. As early as 2003, the MYH9 gene heterozygous mutation defined by Seri M et al. encoded non-muscle myosin heavy chain IIA (NMMHC-IIA) as a MYH9-associated disease (MYH9-RD). The MYH9 gene mutation-associated disease is a type of genetic thrombocytopenia. It is a rare autosomal dominant disease caused by mutations in the MYH9 gene. The patient presented with post-natal platelet reduction and granulocyte inclusion bodies including NMMHC-IIA aggregates. However, in infancy and after adults, many subjects develop additional hearing sensory nerve loss characteristics, cataracts, and/or progressive kidney disease leading to renal failure.

MYH9 Mutation and Disease

At present, 37 mutations have been found in the MYH9 gene, and most of them are mutations, missense mutations, in-frame deletions or replication. Common mutation sites are concentrated in exons 1, 16, 26, 30, 38 and 40, including p.S96L, p.R702C, p.R702H, p.R1165C, p.R1165L, p.D1424H, p.D1424N , p.D1424Y, p.E1841K and p.R1933*. The study found that the genotype and phenotype of MYH9-RD are closely related. When the mutation occurs in the S1 segment, the patient's clinical manifestations are severe giant thrombocytopenia, and the risk of chronic renal failure and neurological deafness is higher; when the mutation occurs in LMM, the patient usually appears to be mild to Moderate giant thrombocytopenia, and the risk of non-hematologic complications is low. In addition, phenotypes caused by changes in amino acids at the same mutation site in MYH9 may vary. Verver et al. found that patients with p.R702C mutations had worse neurological symptoms than patients with p.R702H mutations. Pecci et al. found that patients with p.D1424H and p.D1424Y mutations had significantly higher risk of non-hematologic complications than patients with p.D1424N mutations. Even patients with the same family will have clinical manifestations that differ.

MYH9 and Kidney Disease

In the kidney, MYH9 is expressed in glomeruli (especially in podal cells), renal tubules, and peripheral capillaries. Accumulation of normal myosin in podocytes and perhaps mesangial cells, abnormal myosin accumulation and destruction of podocytosis and cytoskeleton of renal tubular epithelial cells can lead to the progression of renal disease. The study found that individual MYH9 gene mutation, renal biopsy electron microscopy showed that focal foot cell foot process disappeared, foot cell hiatus septum was absent, indicating foot cell damage.

Studies have found that African-Americans with non-diabetic ESRD are more susceptible than ESRD, suggesting that the mechanism by which chronic kidney disease progresses from onset to ESRD is not only caused by external stimuli. The incidence of focal segmental glomerular sclerosis (FSGS) FSGS increased, accounting for 3% of ESRD. Afro-Americans suffer from single-shot FSGS four times that of other Americans, and studies have shown that genetic factors contribute to these differences.

References:

  1. Fujita, T. , Kitaura, F. , & Fujii, H. . (2015). A critical role of the thy28-myh9 axis in b cell-specific expression of the pax5 gene in chicken b cells. PLoS ONE, 10(1), e0116579.
  2. Pecci A, Klersy C, Gresele P, Lee KJD, De Rocco D, et al. (2014). myh 9‐related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype–phenotype correlations. Human Mutation, 35(2), 236-247.
  3. Verver, E. J., Topsakal, V., Kunst, H. P., Huygen, P. L., Heller, P. G., & Pujol-Moix, N., et al. (2016). Nonmuscle myosin heavy chain iia mutation predicts severity and progression of sensorineural hearing loss in patients with myh9-related disease. Ear Hear, 37(1), 112-120.

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