What is the myh9 (myosin heavy chain 9) gene?

MYH9 Gene: Definition and Clinical Significance

The MYH9 gene encodes non-muscle myosin heavy chain IIA (NMMHC-IIA), a cytoplasmic contractile protein essential for generating intracellular force and regulating the actin cytoskeleton, with mutations causing MYH9-related disease characterized by macrothrombocytopenia and variable systemic manifestations. 1

Gene Structure and Protein Function

MYH9 is located on chromosome 22q12.3-13 and contains 40 coding exons that produce a protein of approximately 1960 amino acids. 2, 3 The encoded NMMHC-IIA protein consists of two main functional domains:

• Motor domain: Located at the N-terminal region, responsible for ATP hydrolysis and actin-binding activity 1
• Coiled-coil rod (tail) domain: Extends through the C-terminal region, mediating protein dimerization and interactions with other cellular components 2

The protein participates in critical cellular processes including cell division, migration, adhesion, and maintenance of cell shape through regulation of the actin cytoskeleton. 1

Tissue Expression Pattern

MYH9 is widely expressed throughout the body, with particularly high levels in kidney, liver, lung, and spleen, but notably absent in skeletal muscle and testis. 3

In the kidney specifically:

• Expressed in glomerular visceral epithelial cells (podocytes), endothelial cells, and peritubular vessels 2
• Present during fetal kidney development in the S-shaped body stage 2
• This renal expression pattern explains why MYH9 mutations frequently cause progressive nephritis 2

MYH9-Related Disease

Mutations in MYH9 cause an autosomal dominant disorder affecting multiple organ systems, with all patients presenting from birth with macrothrombocytopenia (large platelets and low platelet counts). 4, 5

Clinical Manifestations

The disease encompasses four historically distinct but overlapping syndromes—May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome—now recognized as a single disease spectrum: 5

• Macrothrombocytopenia: Present in 100% of affected individuals from birth 5
• Döhle-like leukocyte inclusions: Cytoplasmic inclusion bodies visible in white blood cells (not present in all cases) 2, 5
• Progressive nephritis: Can lead to end-stage renal failure, develops in infancy or adulthood depending on mutation location 4, 2
• Sensorineural deafness: Typically presenile onset 4, 5
• Presenile cataracts: Occurs in some patients 4, 5

Genotype-Phenotype Correlations

The location of the mutation within the MYH9 gene strongly predicts disease severity and clinical course: 4

• Motor domain mutations (upstream, approximately amino acids 1-1400): Associated with severe thrombocytopenia and high risk of nephritis and deafness before age 40 years 4
• Tail domain mutations (downstream, after approximately amino acid 1400): Associated with milder thrombocytopenia and significantly lower risk of systemic complications 4

Specific mutation hotspots show distinct clinical patterns: 4

• Residue 1933 mutations: Do not cause kidney damage or cataracts; deafness only in elderly 4
• Residue 702 mutations: Cause severe thrombocytopenia with juvenile-onset nephritis and deafness 4
• Residues 1424 or 1841 mutations: Result in intermediate clinical severity 4, 2

Bleeding Risk

The bleeding tendency in MYH9-related disease is usually moderate, with menorrhagia and easy bruising being most common. 5 However, defective platelet adhesion and thrombus formation under shear conditions can occur. 6

Diagnostic Pitfalls

The greatest clinical risk is misdiagnosis as chronic autoimmune thrombocytopenia, leading to inappropriate immunosuppressive therapy or splenectomy. 5 Key distinguishing features include:

• Large platelet size on blood smear (macrothrombocytopenia) 6, 5
• Presence from birth rather than acquired 5
• Family history consistent with autosomal dominant inheritance 5
• Possible leukocyte inclusions on peripheral smear 6, 2

Role in Other Diseases

Beyond MYH9-related disease, variants in this gene have been implicated in chronic kidney disease susceptibility, particularly in African ancestry populations (though APOL1 was subsequently identified as the true causal gene in that locus), non-syndromic deafness, and potentially cancer. 6, 1

In familial thoracic aortic aneurysm and dissection, MYH11 (smooth muscle myosin heavy chain 11, not MYH9) is the relevant gene, particularly when associated with patent ductus arteriosus. 6 This distinction is important to avoid confusion between these different myosin genes.