MYO6

MYO6 encodes myosin VI, a unique actin-based motor protein that moves in the reverse direction along actin filaments. This protein enables specialized roles in intracellular transport, cell structure, and sensory function.

Its distinct directionality and regulatory domains make it critical for hearing, vision, and vesicle trafficking, and increasingly relevant in cancer biology and therapeutic resistance.

What is MYO6 (Myosin VI)?

The MYO6 gene on chromosome 6q14.1 encodes myosin VI, an unconventional member of the actin-based myosin motor protein family. 

Unlike most myosins, which move toward the plus (barbed) end of actin filaments, myosin VI is unique in its ability to move in the reverse direction—toward the minus end. This directional distinction is key to its specialized roles in intracellular trafficking, organelle positioning, endocytosis, and cell structure maintenance.

MYO6: A Unique Myosin with Diverse Cellular Roles

Myosin VI is a ~149.7 kDa protein composed of 1,294 amino acids. 

It contains three main structural domains: a motor domain responsible for ATP hydrolysis and actin binding, a neck region with a calmodulin-binding IQ motif, and a C-terminal tail that mediates cargo binding and regulatory interactions. This tail region includes adaptor- and ubiquitin-binding motifs and nuclear localization signals.

MYO6 is primarily localized in the cytosol, trans-Golgi network, clathrin-coated vesicles, endosomes, and autophagosomes. It is also found in cell projections such as microvilli, filopodia, and ruffles, particularly in polarized epithelial cells and sensory structures like stereocilia.

Tissue Expression & Function

MYO6 is expressed across a wide range of tissues and performs distinct functions depending on cellular context:

• Inner ear hair cells: Maintains the structure of stereocilia, which are critical for mechanosensory signal transduction.
• Retina: May support photoreceptor function and visual signaling.
• Neurons: Involved in neurite extension, AMPA receptor trafficking, and cytoskeletal remodeling.
• Epithelial cells: Regulates endocytosis, vesicle trafficking, and the integrity of the apical brush border.
• Cancer and immune cells: Modulates focal adhesion dynamics, survival signaling, and immune cell interaction.

When is MYO6 Testing or Research Relevant?

MYO6 testing may be relevant in the following settings:

Clinical Testing

MYO6 genetic testing is clinically relevant in evaluating nonsyndromic sensorineural hearing loss, especially when inheritance patterns suggest autosomal recessive (DFNB37) or autosomal dominant (DFNA22) transmission.

Testing may also be considered in patients presenting with both hearing loss and hypertrophic cardiomyopathy, a phenotype associated with certain MYO6 variants.

Research Applications

MYO6 is being studied in the context of multiple human conditions:

• Hearing loss: Both dominant and recessive mutations are well-characterized causes of hereditary deafness.
• Vision impairment: Suggested role in photoreceptor maintenance and retinal signaling.
• Neurological disorders: Potential involvement in neurodevelopment and synaptic function.
• Cancer:
  
  • In clear cell renal cell carcinoma (ccRCC), MYO6 is significantly downregulated and correlates with poor survival.
  • In castration-resistant prostate cancer (CRPC), MYO6 is upregulated and promotes therapy resistance via the androgen receptor (AR)–FAK pathway.

MYO6 Genetic Testing: Test Procedure and Interpretation

Testing for MYO6 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MYO6 genetic testing are considered to be without mutations that can alter the activity of the MYO6 proteins.

What Do Mutations in MYO6 Mean?

MYO6 mutations may have the following clinical significance: 

Hearing Loss

MYO6 mutations are associated with two main hereditary hearing loss conditions:

• Autosomal Recessive (DFNB37):
  
  • Congenital, severe to profound, bilateral hearing loss
  • Typically stable or slowly progressive
• Autosomal Dominant (DFNA22):
  
  • Postlingual, progressive, high-frequency hearing loss
  • Onset often in adolescence or adulthood

These phenotypes arise from loss-of-function or dominant-negative effects on myosin VI, disrupting its role in stereocilia development and maintenance in cochlear hair cells.

Other Conditions

In cancer, MYO6 expression levels influence prognosis and treatment outcomes. In CRPC, androgen receptor signaling directly upregulates MYO6, promoting epithelial–mesenchymal transition (EMT), invasion, and enzalutamide resistance through focal adhesion kinase (FAK) activation. 

Conversely, in ccRCC, MYO6 is downregulated and serves as a potential prognostic biomarker. Low expression correlates with poor survival, advanced tumor grade and stage, and altered immune microenvironments.

Cellular Disruption

Loss or dysfunction of MYO6 affects:

• Stereocilia function in the cochlea
• Vesicle and cargo transport
• Actin cytoskeletal dynamics
• Transcriptional regulation
• Autophagy and mitophagy
• Immune cell interactions and signaling pathways

What Does the Absence of Specific Studied MYO6 Variants Mean?

The absence of known pathogenic MYO6 variants does not exclude a genetic cause of hearing loss or other MYO6-related conditions. 

Hearing loss is genetically heterogeneous, and mutations in other genes, or uncharacterized regions of MYO6, may still be responsible. Therefore, MYO6 results should be interpreted in the context of clinical findings, family history, and broader genetic testing.

Summary for Clinicians

MYO6 encodes a reverse-direction myosin essential for intracellular transport, structural maintenance, and signaling in specialized cell types. Mutations are a known cause of hereditary hearing loss, and MYO6 plays emerging roles in cancer biology, particularly in prostate and renal carcinomas.

Clinical Applications

Genetic testing for MYO6 should be considered in:

• Progressive or congenital nonsyndromic hearing loss
• Hearing loss with possible cardiac involvement
• Biomarker potential:
  
  • Low MYO6 expression: Poor prognosis in ccRCC
  • High MYO6 expression: Enzalutamide resistance in CRPC

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