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MYO15A
myosin XVA
MYO15A is located on the short (p) arm of chromosome 17, at band 17p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
MYO15A (myosin XVA) encodes a member of the unconventional myosin superfamily, a group of motor proteins that transport cellular cargo along actin filaments. Located on chromosome 17p11.2, this gene produces a large protein of 3,530 amino acids that is predominantly expressed in the sensory hair cells of the inner ear. The protein is essential for the proper formation of stereocilia, the mechanosensory projections that detect sound vibrations and convert them into electrical signals for the brain. Disruption of MYO15A function impairs stereocilia development, leading to congenital hearing impairment. The gene is particularly relevant in the context of inherited hearing loss, where it represents one of several genes contributing to early-onset deafness.
What the gene does
Myosin XVA functions as a molecular motor that transports proteins and other molecules to the tips of stereocilia during their formation and maintenance. Stereocilia are organised into bundles of graduated heights on the surface of cochlear and vestibular hair cells, and their precise structure is essential for mechanotransduction in hearing and balance. The protein delivers cargo necessary for stereocilia elongation and stabilisation, ensuring that these structures reach their appropriate lengths. Without functional myosin XVA, stereocilia remain abnormally short and disorganised, preventing effective sound detection. The motor domain of the protein binds to actin filaments within the stereocilia, while the tail region is thought to interact with cargo proteins. This transport activity is particularly critical during inner ear development, when stereocilia bundles are first established, though the protein may also contribute to ongoing maintenance throughout life.
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Chromosome location
MYO15A is located on the short arm of chromosome 17 at position 17p11.2. This chromosomal region spans a genetically dense area containing multiple genes. The MYO15A gene itself is relatively large, reflecting the size of the protein it encodes. The genomic structure includes numerous exons that are spliced together to produce the mature messenger RNA template for protein synthesis.
Protein structure
The MYO15A protein comprises 3,530 amino acids organised into several distinct functional regions. The myosin motor domain (amino acids 1222-1899) contains the ATP-binding and actin-binding sites required for motor activity, with a specific actin-binding region at positions 1792-1799. A coiled coil segment (amino acids 1323-1350) is embedded within the motor domain. The neck or regulatory domain (amino acids 1888-2029) includes three IQ motifs (IQ 1: 1902-1924; IQ 2: 1925-1954; IQ 3: 1955-1976) that bind calmodulin or calmodulin-like proteins, which regulate motor function in response to calcium levels. The tail region (amino acids 2030-3530) contains a MyTH4 domain (amino acids 2065-2217), which is characteristic of certain unconventional myosins and may mediate protein-protein interactions. Multiple disordered regions are present at positions 1-46, 615-710, 730-1057, 2311-2381, 2414-2446, and 2490-2509, which may provide structural flexibility or regulatory interfaces.
Key variants
Pathogenic variants in MYO15A are associated with autosomal recessive non-syndromic hearing loss, designated DFNB3. Both loss-of-function variants (such as nonsense or frameshift changes) and missense variants affecting critical functional domains have been identified. The spectrum of variants reflects the gene's large size, with pathogenic changes reported across multiple exons. Carrier status for a single pathogenic variant typically does not affect hearing, as two altered copies are required to cause the condition.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.2278dup | p.Ala760fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.2748dup | p.Glu917fs | Pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.7894G>T | p.Val2632Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.8296C>T | p.Arg2766Ter | Pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.8378C>A | p.Ser2793Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.8459+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.1838del | p.Lys613fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.358_361del | p.Leu120fs | Pathogenic | ★☆☆☆ | not provided |
c.6130del | p.Asp2044fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
c.6408G>A | p.Trp2136Ter | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 3 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
MYO15A-related hearing loss typically presents as congenital, bilateral sensorineural deafness affecting both ears from birth or early infancy. The hearing impairment is generally severe to profound and non-progressive, meaning it does not worsen significantly over time. Because the condition is non-syndromic, affected individuals do not exhibit other systemic health problems related to the genetic change. The prevalence of MYO15A variants varies across populations, with certain variants observed more frequently in specific ethnic groups due to founder effects.
No disease links recorded for this gene in our reference set.
UK clinical status
MYO15A is included in the NHS Genomic Medicine Service monogenic hearing loss panel (green classification, version R67). This green rating indicates strong evidence supporting the gene's role in inherited hearing impairment, and it may be analysed as part of clinical genetic testing for individuals with unexplained hearing loss, particularly when a family history suggests autosomal recessive inheritance. Testing is typically coordinated through audiology and clinical genetics services.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is MYO15A-related hearing loss inherited?
MYO15A-related hearing loss follows an autosomal recessive pattern, meaning an individual must inherit two pathogenic variants (one from each parent) to be affected. Parents who each carry one variant typically have normal hearing and a 25% chance with each pregnancy of having an affected child.
Can MYO15A variants be detected through newborn hearing screening?
Newborn hearing screening can identify hearing loss caused by MYO15A variants, as the condition is typically present from birth. However, the screening detects the hearing impairment itself, not the genetic cause. Genetic testing is a separate process that can determine whether MYO15A or another gene is responsible.
Are there treatments for MYO15A-related hearing loss?
While there is no cure that restores normal MYO15A protein function, cochlear implants and hearing aids can provide significant benefit for many individuals with severe to profound hearing loss. Early intervention with these technologies, along with speech and language support, helps optimise communication development.