MYO7A — Myosin VIIA

The MYO7A gene provides instructions for making a protein called myosin VIIA. This protein acts like a tiny molecular motor inside cells, moving along tracks made of another protein called actin to transport important materials from one part of the cell to another. Myosin VIIA is especially important in two parts of the body: the inner ear and the retina (the light-sensitive tissue at the back of the eye). In the inner ear, it helps build and maintain the tiny hair-like structures that detect sound and help us keep our balance. In the eye, it helps move pigment and other essential molecules that keep the light-sensing cells healthy and functioning properly. When the MYO7A gene is mutated, the myosin VIIA protein either doesn't work correctly or isn't produced at all. Without this functioning motor protein, the hair cells in the inner ear cannot develop properly, leading to hearing loss and balance issues. In the eye, the lack of myosin VIIA causes a buildup of materials and a breakdown of the light-sensing cells, leading to a progressive loss of vision known as retinitis pigmentosa. The most common condition caused by MYO7A mutations is Usher syndrome type 1B, which involves profound hearing loss from birth, severe balance problems, and vision loss that begins in childhood. Less commonly, some MYO7A mutations only affect hearing without causing vision or balance problems. For patients and families, a diagnosis of a MYO7A-related disorder means managing both hearing and vision challenges. Children with Usher syndrome type 1B are typically born deaf and may experience delays in walking due to balance issues. Vision loss usually starts with night blindness in childhood and progresses to a loss of side (peripheral) vision over time. Most MYO7A conditions are inherited in an autosomal recessive pattern, meaning a child must inherit two mutated copies of the gene (one from each parent) to have the disorder. Parents of an affected child are usually carriers who do not have symptoms themselves, but they have a 25% chance of having another affected child in future pregnancies. Genetic counseling is an important step for families to understand these risks and explore available support and early intervention strategies.

Gene description: This gene encodes an unconventional myosin that plays a crucial role in the development and function of the inner ear and retina.

Patient and family guide: The MYO7A gene provides instructions for making a protein called myosin VIIA. This protein acts like a tiny molecular motor inside cells, moving along tracks made of another protein called actin to transport important materials from one part of the cell to another. Myosin VIIA is especially important in two parts of the body: the inner ear and the retina (the light-sensitive tissue at the back of the eye). In the inner ear, it helps build and maintain the tiny hair-like structures that detect sound and help us keep our balance. In the eye, it helps move pigment and other essential molecules that keep the light-sensing cells healthy and functioning properly. When the MYO7A gene is mutated, the myosin VIIA protein either doesn't work correctly or isn't produced at all. Without this functioning motor protein, the hair cells in the inner ear cannot develop properly, leading to hearing loss and balance issues. In the eye, the lack of myosin VIIA causes a buildup of materials and a breakdown of the light-sensing cells, leading to a progressive loss of vision known as retinitis pigmentosa. The most common condition caused by MYO7A mutations is Usher syndrome type 1B, which involves profound hearing loss from birth, severe balance problems, and vision loss that begins in childhood. Less commonly, some MYO7A mutations only affect hearing without causing vision or balance problems. For patients and families, a diagnosis of a MYO7A-related disorder means managing both hearing and vision challenges. Children with Usher syndrome type 1B are typically born deaf and may experience delays in walking due to balance issues. Vision loss usually starts with night blindness in childhood and progresses to a loss of side (peripheral) vision over time. Most MYO7A conditions are inherited in an autosomal recessive pattern, meaning a child must inherit two mutated copies of the gene (one from each parent) to have the disorder. Parents of an affected child are usually carriers who do not have symptoms themselves, but they have a 25% chance of having another affected child in future pregnancies. Genetic counseling is an important step for families to understand these risks and explore available support and early intervention strategies.

Gene function: MYO7A is essential for the proper function of photoreceptor cells and retinal pigment epithelium (RPE). It is involved in melanosome transport within the RPE and phagocytosis of photoreceptor outer segments, processes critical for maintaining retinal health and visual cycle. Mutations disrupt these functions, leading to photoreceptor degeneration and vision loss.

Protein structure: The MYO7A gene encodes myosin VIIA, a large unconventional myosin motor protein consisting of 2,215 amino acids. The protein is structurally organized into three main regions: a highly conserved N-terminal motor (head) domain, a neck region, and a divergent C-terminal tail domain. The motor domain contains the ATP-binding site and the actin-binding region, which are essential for the protein's ATPase activity and its ability to move along actin filaments. The neck region contains five IQ motifs, which serve as binding sites for calmodulin and other light chains, regulating the motor's activity in a calcium-dependent manner. The long C-terminal tail domain is responsible for cargo binding and protein-protein interactions. It includes a short coiled-coil region that facilitates dimerization, followed by two large repeats, each containing a MyTH4 (myosin tail homology 4) domain and a FERM (band 4.1, ezrin, radixin, moesin) domain, separated by an SH3 (Src homology 3) domain. These tail domains are crucial for interacting with other Usher syndrome proteins, such as harmonin and SANS, to form the functional macromolecular complexes required in the inner ear and retina.

Molecular function: The MYO7A gene encodes myosin VIIA, an unconventional myosin motor protein that moves along actin filaments. Myosin VIIA is composed of a highly conserved motor (head) domain with ATPase activity, a neck region containing IQ motifs that bind calmodulin, and a divergent tail domain that interacts with various cargo molecules and adapter proteins. The hydrolysis of ATP in the motor domain provides the energy required for the protein to move along actin filaments, allowing it to transport intracellular cargo. In the inner ear, myosin VIIA is a crucial component of the mechanotransduction complex in sensory hair cells. It interacts with other Usher syndrome proteins, such as harmonin (USH1C), cadherin-23 (USH1D), and SANS (USH1G), to form a functional network that anchors the stereocilia and maintains the tension necessary for mechanotransduction. This complex is essential for the proper organization and cohesion of the hair bundles, enabling them to convert mechanical sound waves into electrical signals. In the retina, myosin VIIA plays multiple roles in both the retinal pigment epithelium (RPE) and photoreceptor cells. In the RPE, it is responsible for the apical transport of melanosomes, which are pigment granules necessary for normal vision, and it participates in the phagocytosis of shed photoreceptor outer segment disks. In photoreceptors, myosin VIIA is involved in the transport of opsin molecules and other proteins through the connecting cilium to the outer segment. Defects in these transport processes lead to the accumulation of proteins and the eventual degeneration of photoreceptor cells seen in retinitis pigmentosa.

Expression pattern: The MYO7A gene is widely expressed in various epithelial tissues, with its most critical roles occurring in the inner ear and the retina. In the inner ear, MYO7A is expressed in the sensory hair cells of both the cochlea and the vestibular system. It is specifically localized to the actin-rich stereocilia and the pericuticular necklace, where it is essential for the development, maintenance, and function of the hair bundles required for hearing and balance. In the eye, MYO7A is predominantly expressed in the retinal pigment epithelium (RPE) and the photoreceptor cells. Within the RPE, it is found in the apical microvilli, where it is involved in the transport of melanosomes and the phagocytosis of shed photoreceptor outer segment disks. In photoreceptors, MYO7A localizes to the connecting cilium and calyceal processes, playing a role in the transport of opsins and other vital proteins between the inner and outer segments. The gene is also expressed in other tissues, including the lungs, kidneys, and testis, though its specific functions in these organs are less well-defined.

Mutation spectrum: The mutation spectrum of the MYO7A gene is highly diverse, with over 800 pathogenic variants identified to date. These include missense, nonsense, frameshift, splice-site mutations, and large genomic deletions. Mutations are distributed throughout the entire length of the gene, affecting all functional domains of the myosin VIIA protein, including the motor head, neck, and tail regions. While there are no major universal hotspot regions, certain founder mutations have been identified in specific populations. For example, the R245X mutation is a known founder mutation in the Ashkenazi Jewish population, and the c.2283-1G>T splice-site mutation is prevalent in some African populations. The majority of MYO7A mutations cause Usher syndrome type 1B (USH1B), but a smaller subset of specific missense mutations is associated with the non-syndromic hearing loss phenotypes DFNA11 and DFNB2.

Pathogenic variants: 1. p.Arg245Ter (R245X) - A nonsense mutation that is a well-known founder mutation in the Ashkenazi Jewish population, causing severe Usher syndrome type 1B (USH1B). 2. c.2283-1G>T - A splice-site mutation that is a common founder mutation in indigenous South African populations, responsible for a significant proportion of USH1B cases in this group. 3. p.Arg212His (R212H) - A common missense mutation located in the motor domain of the protein, frequently identified in patients with USH1B. 4. p.Arg212Cys (R212C) - Another frequent missense mutation at the same amino acid position in the motor domain, also causing USH1B. 5. p.Arg244Pro (R244P) - A missense mutation that has been associated with autosomal recessive non-syndromic hearing loss (DFNB2), demonstrating that specific MYO7A variants can cause hearing loss without retinal degeneration.

Clinical significance: Mutations in the MYO7A gene are primarily responsible for Usher syndrome type 1B (USH1B), which is the most common and severe form of Usher syndrome type 1. USH1B is characterized by congenital, profound sensorineural hearing loss, absent vestibular function (leading to delayed motor milestones such as walking), and prepubertal onset of retinitis pigmentosa (RP). The vision loss in RP typically begins with night blindness and progresses to a loss of peripheral vision, eventually leading to legal blindness in adulthood. In addition to USH1B, MYO7A mutations can cause two forms of non-syndromic hearing loss: DFNA11 and DFNB2. DFNA11 is an autosomal dominant condition characterized by postlingual, progressive sensorineural hearing loss that typically begins in childhood or adolescence. DFNB2 is an autosomal recessive condition that can present as either prelingual or postlingual hearing loss, but unlike USH1B, it is not associated with retinitis pigmentosa or vestibular dysfunction. The severity and onset of hearing loss in these non-syndromic forms can vary significantly among affected individuals.

Inheritance: Autosomal Recessive

Chromosomal location: 11q13.5

Genotype-phenotype correlations: Genotype-phenotype correlations for MYO7A are complex and not entirely straightforward. Generally, severe loss-of-function mutations (such as nonsense, frameshift, and splice-site mutations) that result in a complete absence of functional myosin VIIA protein are associated with the severe USH1B phenotype. These patients typically experience profound congenital deafness, absent vestibular function, and early-onset retinitis pigmentosa. Conversely, missense mutations that allow for the production of a partially functional protein are more frequently associated with the milder non-syndromic hearing loss phenotypes (DFNA11 and DFNB2) or atypical, milder forms of Usher syndrome. For example, some missense mutations may retain enough function in the retina to prevent retinitis pigmentosa but not enough in the inner ear to maintain normal hearing, leading to DFNB2. However, significant clinical variability can exist even among individuals with the same MYO7A mutations, suggesting that other genetic or environmental factors may influence disease severity and progression.

Research and therapeutic approaches: Currently, there are no FDA-approved treatments to cure or halt the progression of vision loss in MYO7A-related Usher syndrome (USH1B). Management primarily focuses on early intervention with cochlear implants to address hearing loss, physical therapy for balance issues, and low-vision aids to maximize remaining sight. However, several promising therapeutic strategies are under active investigation in preclinical and clinical stages. Gene therapy is a major focus of research for USH1B. Because the MYO7A gene is too large to fit into a standard adeno-associated virus (AAV) vector, researchers are developing dual-AAV vector systems. In this approach, the gene is split into two halves, delivered by separate AAVs, and reassembled inside the target retinal cells. A Phase 1/2 clinical trial (NCT01505062) investigated the safety and tolerability of a lentiviral vector gene therapy called UshStat (SAR421869) delivered via subretinal injection, though lentiviral approaches have faced challenges with transduction efficiency in photoreceptors. Other experimental approaches include CRISPR/Cas9 gene editing to correct specific MYO7A mutations directly within the patient's cells, and the use of antisense oligonucleotides (ASOs) or small molecules (such as translational read-through inducing drugs for nonsense mutations like R245X). These strategies are currently in preclinical development and aim to restore functional myosin VIIA protein expression to preserve vision in affected individuals.

Diagnostic testing: Diagnosis of MYO7A-related disorders typically involves comprehensive clinical evaluation, including audiological testing, vestibular function assessment, and ophthalmological exams (such as electroretinography and visual field testing). Genetic testing is the definitive method for confirming a diagnosis. This is usually performed using multi-gene panels that include MYO7A and other genes associated with Usher syndrome and non-syndromic hearing loss. Whole exome or whole genome sequencing may also be utilized if panel testing is inconclusive. Genetic counseling is highly recommended for individuals and families affected by MYO7A mutations. Since USH1B and DFNB2 are inherited in an autosomal recessive manner, parents of an affected child are typically obligate carriers and have a 25% chance of having another affected child in subsequent pregnancies. DFNA11 is inherited in an autosomal dominant manner, meaning an affected individual has a 50% chance of passing the mutation to their offspring. Carrier screening is available and particularly relevant for populations with known founder mutations.

Animal models: The primary animal model for studying MYO7A is the shaker-1 (sh1) mouse, which exhibits profound deafness and vestibular dysfunction (head-tossing and circling behaviors) due to disorganized stereocilia in the inner ear. However, shaker-1 mice do not display the severe retinal degeneration seen in human USH1B patients, though they do show mild defects such as mislocalization of rhodopsin and reduced electroretinogram (ERG) amplitudes. Another important model is the zebrafish mariner mutant (myo7aa-/-), which displays balance and hearing defects similar to the mouse model. Unlike the mouse, the zebrafish model exhibits more pronounced photoreceptor degeneration, especially under constant light exposure, making it a valuable model for studying the retinitis pigmentosa aspect of USH1B.

Population genetics: The carrier frequency for MYO7A pathogenic variants in the general population is estimated to be approximately 1 in 165. However, this frequency can be significantly higher in certain populations due to founder effects. For instance, the p.Arg245Ter (R245X) mutation is a known founder mutation in the Ashkenazi Jewish population, leading to a higher carrier rate and prevalence of USH1B in this group. Similarly, the c.2283-1G>T splice-site mutation is a major founder mutation in indigenous South African populations, accounting for up to 43% of Usher syndrome cases in some cohorts. These population-specific frequencies are important considerations for targeted carrier screening and genetic counseling.

Selected references: 1. Weil D, et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature, 1995. PMID: 7870171 2. Gibson F, et al. A type VII myosin encoded by the mouse deafness gene shaker-1. Nature, 1995. PMID: 7870172 3. Hasson T, et al. Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc Natl Acad Sci U S A, 1995. PMID: 7568124 4. Liu XZ, et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet, 1997. PMID: 9171832 5. Boeda B, et al. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J, 2002. PMID: 12456643 6. Williams DS, Lopes VS. The many different cellular functions of MYO7A in the retina. Biochem Soc Trans, 2011. PMID: 21936790 7. Wu L, et al. Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. Science, 2011. PMID: 21311020