Abstract
Deleterious variants of more than one hundred genes are associated with hearing loss including MYO3A, MYO6, MYO7A and MYO15A and two conventional myosins MYH9 and MYH14. Variants of MYO7A also manifest as Usher syndrome associated with dysfunction of the retina and vestibule as well as hearing loss. While the functions of MYH9 and MYH14 in the inner ear are debated, MYO3A, MYO6, MYO7A and MYO15A are expressed in inner ear hair cells along with class-I myosin MYO1C and are essential for developing and maintaining functional stereocilia on the apical surface of hair cells. Stereocilia are large, cylindrical, actin-rich protrusions functioning as biological mechanosensors to detect sound, acceleration and posture. The rigidity of stereocilia is sustained by highly crosslinked unidirectionally-oriented F-actin, which also provides a scaffold for various proteins including unconventional myosins and their cargo. Typical myosin molecules consist of an ATPase head motor domain to transmit forces to F-actin, a neck containing IQ-motifs that bind regulatory light chains and a tail region with motifs recognizing partners. Instead of long coiled-coil domains characterizing conventional myosins, the tails of unconventional myosins have various motifs to anchor or transport proteins and phospholipids along the F-actin core of a stereocilium. For these myosins, decades of studies have elucidated their biochemical properties, interacting partners in hair cells and variants associated with hearing loss. However, less is known about how myosins traffic in a stereocilium using their motor function, and how each variant correlates with a clinical condition including the severity and onset of hearing loss, mode of inheritance and presence of symptoms other than hearing loss. Here, we cover the domain structures and functions of myosins associated with hearing loss together with advances, open questions about trafficking of myosins in stereocilia and correlations between hundreds of variants in myosins annotated in ClinVar and the corresponding deafness phenotypes.
1 Introduction
Sound waves pass through the outer and middle ear providing input signals to the mechanosensory organelles on the apical surface of cochlear hair cells. These organelles represented by cylindrical protrusions called stereocilia are derived during development from microvilli and are aligned in rows of graded heights that synchronously deflect in response to sound vibrations in inner ear fluids (Schwander et al., 2010) (Figures 1A–C). Mechanical sound stimuli are converted by stereocilia into electro-chemical activities in hair cells. With the exception of the tallest row, stereocilia are equipped with mechanotransduction (MET) channels at their distal ends, which are connected to the side of adjacent longer stereocilia by tip-links that gate the MET channels (). Open MET channels allow cations in the endolymph, specifically K+ and Ca2+, to flow into the hair cell cytoplasm. This influx causes a depolarization wave of the plasma membrane that propagates toward the base of hair cells, induces the opening of voltage-dependent Ca2+ channels and finally triggers Ca2+-dependent fusion of glutamate-containing synaptic vesicles at the basal surface of hair cells (; ; ) (Figure 1B).
FIGURE 1
Each stereocilium has a core of unidirectional F-actin tightly packed by actin cross-linkers, including ESPN, PLS1, FSCN2 and XIRP2 (Zheng et al., 2000; Shin et al., 2010; Scheffer et al., 2015; ), and connected to the underneath cuticular plate by a rootlet consisting of F-actin bundled more tightly by TRIOBP4 and TRIOBP5 (; ) (Figure 1C). For stereocilia, the F-actin core is a backbone to resist repeated mechanical stimuli and also a scaffold for various proteins including components of the MET machinery and motor proteins to transport or anchor these components. A similar mechanism is utilized by vestibular hair cells to detect gravity and acceleration as inputs for equilibrioception ().
The myosin superfamily is one of three major families of motor proteins along with the kinesins and dyneins. Only myosins move on F-actin (Sweeney and Holzbaur, 2018). A typical myosin molecule has an ATPase head motor domain to transmit forces to F-actin, a neck containing IQ-motifs that bind regulatory light chains and a tail region to interact with specific partners. Phylogenic analyses have revealed 18 classes of myosins () including class-II “conventional” double-headed myosins initially discovered in skeletal muscle extracts () and other “unconventional” myosins named after the single-headed class-I myosin discovered in Acanthamoeba (Pollard and Korn, 1973). While the tails of class-II myosins consist of a long coiled-coil domain to form a double-headed homodimer, those of unconventional myosins contain various motifs to recognize specific partners and usually have no or only a short coiled-coil domain (). Myosins lacking the coiled-coil domain are “unconventionally” single-headed because they cannot dimerize spontaneously. As another difference from conventional myosins, some unconventional myosins can “walk” on F-actin when dimerized by a short coiled-coil domain (e.g., class V and X) or by cargo bound to the tail (e.g., class VI and VIIA) and can transport vesicles and specific proteins as cargo (Yu et al., 2009; Sakai et al., 2011; ; ). In the human genome, there are about 40 different genes encoding myosins that are grouped into 12 classes, I–III, V–VII, IX, X, XV, XVI, XVIII and XIX (). Abnormal function of these myosins are associated with various diseases including myopathies, colitis, glomerulosclerosis, neurological defects, cancer, blindness and hearing loss ().
In humans, variants of two genes encoding class-II conventional myosins, MYH9 and MYH14, and four genes encoding class-IIIA, -VI, -VIIA and -XVA unconventional myosins, MYO3A, MYO6, MYO7A and MYO15A, are presently associated with autosomal dominant or recessive nonsyndromic sensorineural hearing loss (Table 1). Variants of MYO7A are also associated with autosomal recessive Usher syndrome type 1 characterized by congenital sensorineural hearing loss, vestibular dysfunction and progressive retinitis pigmentosa (Weil et al., 1995). While the functions of MYH9 and MYH14 in the inner ear are still being debated, MYO3A, MYO6, MYO7A, MYO15A and some class-I myosins (e.g., MYO1C) are expressed in inner ear hair cells and are crucial for developing and maintaining functional stereocilia by anchoring and/or transporting specific partners on the F-actin core (Table 2). Decades of studies have identified the cargo of these unconventional myosins in a stereocilium and elucidated their contribution to normal hearing including (1) formation of the MET machinery, (2) elongation of the F-actin core and (3) tethering the plasma membrane and the ankle links to the F-actin core () (Figure 1D). However, less is understood about how these myosins traffic in a stereocilium using their motor function. For example, it is unknown whether or not MYO7A functions as a dimer (or perhaps as an oligomer) in a stereocilium although cargo-mediated dimerization is reported for this myosin and likely utilized in the retina (; Sakai et al., 2011).
TABLE 1
| Gene | Locus | Duty ratio | Rate-limiting step | Velocity (µm/s) † | References |
|---|---|---|---|---|---|
| MYO1A | Refuted | 0.05 | Pi release | 0.07–0.1 at 37°C | , Ostap and Pollard (1996), , , Patton et al. (2016) |
| MYO1C | Disputed | 0.11 | Pi release | ∼0.06 at 37°C | Stauffer et al. (2005), , , , |
| MYO1F | Disputed | N.A. | N.A. | N.A. | |
| MYO3A | DFNB30 | 0.25 (0.91‡) | ADP release | 0.11 at RT | Walsh et al. (2002), , , Salles et al. (2009), |
| MYO6 | DFNA22, DFNB37 | 0.8 (monomer) | ADP release | −0.131 (monomer), −0.307 (dimer) at 30°C§ | , Self et al. (1999), , , , , Morris et al. (2003), Sakaguchi et al. (2008) |
| MYO7A | DFNA11, DFNB2, USH1B | 0.9 (monomer) | ADP release | 0.19 at RT | Weil et al. (1995), , Weil et al. (1997), Udovichenko et al. (2002), Watanabe et al. (2006), , , , |
| MYO15A | DFNB3 | ∼0.5 | ATP binding | ∼0.43 at 30°C | Wang et al. (1998), , Mogensen et al. (2007), Zampini et al. (2011), , , Moreland et al. (2021) |
| MYH9 | DFNA17 | ∼0.29 | Attachment to actin or Pi release¤ | 0.29 at 30°C | , Wang et al. (2000), Yengo et al. (2012) |
| MYH14 | DFNA4A | ∼0.34 | Attachment to actin or Pi release¤ | 0.090 at 30°C | , , Yengo et al. (2012) |
| (MYO5A) | * | 0.7 (monomer) | ADP release | 0.311 at 23°C | , |
| (MYO10) | * | 0.16, 0.6 ¶ | N.A. | 0.17 at 25°C€ | , , |
Myosins associated (or potentially associated) with human hearing loss and their kinetic properties. Prepared based on data published in reviews (O'Connell et al., 2007; ). The italic values indicate gene names.
*Listed for comparison.
†F-actin sliding assay.
‡contains the N-terminal kinase domain.
§Moves toward the pointed end of F-actin.
¤In solution as discussed in a comparative study (Yengo et al., 2012).
¶Another study supports the high duty ratio of MYO10 (Takagi et al., 2014).
€(; ).
TABLE 2
| Myosin | Presumed functions in the inner ear | N-terminal splicing variants | Major phenotypes in knockout mice | References |
|---|---|---|---|---|
| MYO1A | Unclear | Not found yet | Knockout mice show no overt phenotypes | Stauffer et al. (2005), Tyska et al. (2005), Solanki et al. (2021) |
| MYO1C | Adaptation of MET channels | Not found yet | Homozygous knockout is associated with visual impairment. Hearing loss has not been reported in peer-reviewed journals | Stauffer et al. (2005), Solanki et al. (2021) |
| MYO1F | Unclear | Not found yet | Knockout mice show impaired immune responses, but hearing loss is not reported | |
| MYO3A | Transports factors to elongate the F-actin core | Not found yet | Double knockout of Myo3a and Myo3b results in profound deafness and a dysmorphic staircase architecture of stereocilia | Salles et al. (2009), |
| MYO6 | Tethers plasma membrane to the F-actin core, keeps stereocilia in place and mediates vesicle transport including endocytosis | Not found yet | Loss of MYO6 function results in profound hearing loss and stereocilia bifurcated or fused with each other | , , Self et al. (1999), , , , , Morris et al. (2003), Sakaguchi et al. (2008) |
| MYO7A | Helps to form tip-link and MET channel complexes and to tether ankle links during development | MYO7A-C, MYO7A-S | Mice lacking the MYO7A function (e.g., Shaker-1 mice) develop severely deformed stereocilia and show profound hearing loss | Weil et al. (1995), , Weil et al. (1997), Self et al. (1998), Udovichenko et al. (2002), Watanabe et al. (2006), , , , |
| MYO15A | Transport factors to elongate the F-actin core, nucleates actin monomers and maintains the length of mechanotransducing stereocilia | MYO15A-1, MYO15A-2, MYO15A-3 | Mice lacking the MYO15A function (e.g., Shaker-2 mice) show short stereocilia and profound hearing loss | Wang et al. (1998), , , , Mogensen et al. (2007), Zampini et al. (2011), , , , Moreland et al. (2021) |
| MYH9 | Unclear | Not found yet | Myh9-null mice are embryonic lethal. Mice with mutant Myh9 show a phenotype resembling human MYH9-related disease including platelet dysfunction and mild hearing loss | , Wang et al. (2000), , Yengo et al. (2012), Zhang et al. (2012) |
| MYH14 | Unclear | Not found yet | Myh14-null mice are susceptible to noise-induced hearing loss | , , Yengo et al. (2012), |
Presumed functions, N-terminal splicing variants and major phenotypes in mouse models.
Variants of these myosin genes affecting the coding regions can result in sensorineural hearing loss through amino-acid sequences altered by nonsense, frameshift and missense mutations and also by in-frame deletions and insertions. Variants in noncoding regions can also result in hearing loss by damaging splicing of the primary mRNA transcript or by altering its expression levels (; Walavalkar and Notani, 2020). Detecting and validating putative regulatory variants of a human gene associated with a disorder is challenging (Zhang and Lupski, 2015). One open question in the hearing research field is how a specific variant in these myosin genes correlates with the mode of inheritance and the severity of a clinical phenotype. For example, variants of MYO7A are associated with both autosomal dominant (DFNA) and recessive (DFNB) nonsyndromic hearing loss as well as Usher syndrome type 1 (USH) (Weil et al., 1995; ; Weil et al., 1997). Phenotypes are different among the MYO7A variants associated with autosomal DFNB hearing loss in severity and threshold at each frequency and also in the age of onset (Tamagawa et al., 2002; Riazuddin et al., 2008; Schultz et al., 2011). One approach to clarify the phenotypic spectrum of variants is to use databases, such as ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), the Deafness Variation Database (https://deafnessvariationdatabase.org/) and gnomAD (https://gnomad.broadinstitute.org/), which comprehensively curate variants with information including pathogenicity and clinical outcomes. Such databases can even point to a “hotspot” of variants in a domain whose function is not fully understood. For example, see MYO15A variants in Figure 6C. In this review, using ClinVar as a source of curated variants of myosin genes associated with human hearing loss, we describe the association between various myosins and hearing loss including recent advances in protein structure and function. Also discussed are open questions about trafficking of myosins in a stereocilium.
2 Domain structure and kinetic properties of myosins
A myosin monomer consists of an ATPase motor domain, a neck region that binds regulatory light chains and a tail region that interacts with specific partners. The motor domain consists of four subdomains, the N-terminal domain, the upper 50-kDa domain, the lower 50-kDa domain and the converter domain as previously reviewed () (Figure 2A). The N-terminal domain of class-II and class-VI myosins have SRC Homology 3 (SH3)-like β-barrel domains (; ; Niu et al., 2024), which are also reported for class-V, -XI, -XXII and -XXIV myosins (https://www.ebi.ac.uk/interpro/entry/InterPro/IPR004009/). The SH3-like domains of class-II myosins interact with the N-terminal extension of ELC () while those of class-VI myosins interact with their own tails to take on a backfolded autoinhibitory state (Niu et al., 2024). The cleft between the upper and lower 50-kDa domains acts as an interface with F-actin during a stroke and is the active site for ATP hydrolysis (Rayment et al., 1996) mediated by three highly-conserved loops, the phosphate binding loop (P-loop), Switch-1 and Switch-2 () (Figure 2B). Switch-2 undergoes a large conformational change to open and close the “back-door exit” to release the inorganic phosphate (Pi) from the cleft (Yount et al., 1995). The converter domain contains an α-helix that forms a lever arm with a long helix in the neck (Sweeney and Houdusse, 2010) and amplifies the small conformational change at the active site into a large stroke (Preller and Manstein, 2013).
FIGURE 2
To transmit force to F-actin, myosin repeats a cycle of hydrolyzing ATP to ADP + Pi accompanying the conformational change of the motor domain () (Figure 2C). In addition to the speed of the ATPase cycle, which can be roughly evaluated by the F-actin gliding assay, the duty ratio is another important parameter defined as the proportion of the ATPase cycle that the motor domain remains strongly bound to F-actin (O'Connell et al., 2007). A high duty ratio greater than ∼0.5 is considered to be a necessary, but not sufficient, requirement for a myosin to show processive movements on F-actin (O'Connell et al., 2007; Pollard and Lord, 2014). The cleft in the motor domain is a mutational “hotspot” for variants associated with human hearing loss. Missense mutations in the MYO7A and MYO15A motor domains causing human and mouse hearing loss often affect the residues facing the cleft (Sellers, 2000). An additional complexity is found in class-VI myosins, which have an insertion called the “reverse gear” between the converter and lever arm. MYO6 is the only myosin that moves toward the pointed end of F-actin (Wells et al., 1999) (see Figure 2E, MYO6).
The neck region consists of a long helix connected to the α-helix in the converter domain (Sweeney and Houdusse, 2010). The length and stability of the helix is a factor determining the step size of a myosin stroke (Sakamoto et al., 2005). The neck region contains α-helical IQ motifs with a consensus sequence, [I,L,V]QXXXRGXXX [R,K] (), or often noted more strictly for myosins, IQXXXRGXXXR (). The IQ motifs interact with members of the EF-hand calcium-binding protein family including ELC, RLC and CaM (; ). All heavy chains of conventional class-II myosins, including MYH9 and MYH14, have two IQ motifs, IQ1 and IQ2, which interact with ELC and RLC, respectively, at high specificity (Rayment et al., 1993; ). Unconventional myosins have up to six IQ motifs depending on the class of myosins although some classes of myosins lack IQ motifs (e.g., class XIV and XVII) or have a different number of IQ motifs within the classes (e.g., class I and XIII) (). Among the myosins related to the inner ear function, interaction with CaM (class IC, VI, III and VIIA) and ELC (class IC, VI and VIIA) are reported (). Two of the three IQ motifs of mouse MYO15 interact with CaM, RLC and ELC but preferably with RLC and ELC (). Some light chains can regulate the power transmission from the motor domain to the tail. For example, CaM bound to the fifth IQ of MYO7A “slide” toward the N-terminus in the presence of Ca2+ and reduce the rigidity between IQ5 and the adjacent single α-helix (SAH) ().
The C-terminal tail regions function as an interface for various partners including myosin itself (i.e., dimerization or multimerization) and cargo (Figures 2D–F). Class II conventional myosins MYH9 and MYH14 have a long coiled-coil tail of various lengths to dimerize with each other () (Figure 2D). These heavy chain dimers can multimerize to form a bipolar thick filament as a part of contractile actomyosin structures (; ). In contrast, the tails of unconventional myosins are different between classes and even among myosins within a class and interact with different “cargo” proteins () (Figures 2E,F). Cargo of the unconventional myosins MYO7A and MYO15A include scaffolding proteins, such as harmonin, SANS and WHRN, to form a network of interactions referred to as an “interactome” (see Figure 3A; Figure 5A; Figure 6A and the next section). Compared with conventional myosins, only a few classes of unconventional myosins have a coiled-coil domain to form a filament (class XVIII) or to walk independently as a parallel dimer (class V) or as an antiparallel dimer (class X) () (Figure 2F). Although five unconventional myosins (class V, VI, VII, X and XVIII) encoded in the human genome have a predicted coiled-coil domain in the tail on the C-terminal side of the IQ motifs (Peckham, 2011), some of these coiled-coil domains are likely to function as a single α-helix (SAH) just to extend the lever arm (Simm et al., 2017). For example, MYO6 can dimerize through their cargo, such as Dab2, bound to the C-terminal globular domain of the tail (Yu et al., 2009) and use SAH to extend the lever arm (Mukherjea et al., 2009). MYO7A can also dimerize via MYRIP in vertebrates (via M7BP in Drosophila) bound to the tail and likely use SAH to extend the lever arm although SAH itself retains weak dimerization activity (Sakai et al., 2011; ). In addition, tails of some myosins can inhibit the motor function. MYO5A, MYO6 and MYO7A can take a compact backfolded conformation until cargo binds to the tail to unleash motor function (Thirumurugan et al., 2006; Spink et al., 2008; Umeki et al., 2009).
FIGURE 3
A few myosins have extensions of various length at the N-terminus of the motor domain. Among the myosins associated with human hearing loss, MYO3A has a 30-kDa kinase domain at the N-terminus. In addition, some myosins have variation at the N-terminus caused by alternative splicing of the primary mRNA transcript (Figure 5B; Figure 6B). For MYO7A, presently two isoforms have been identified, the canonical isoform with an eleven amino-acid extension at the N-terminus (MYO7A-C) and a short isoform without it (MYO7A-S) (Figure 5B). There is speculation that MYO7A-C, mainly expressed in IHCs, is responsible for positioning the MET complex (). MYO15A also has at least three isoforms, an isoform with a large 133-kDa N-terminal domain (MYO15A-1), a short isoform without it (MYO15A-2) and an isoform with a novel 6-kDa N-terminal domain (MYO15A-3) (; Rehman et al., 2016; Moreland and Bird, 2022) (Figure 6B). As discussed in the next section, these three isoforms have different localizations and functions in hair cells. For MYO7A and MYO15A, missense variants in the N-terminal extension are associated with hearing loss demonstrating importance of this sequence for normal hearing in humans (Figure 5C; Figure 6C). In the next section, in greater detail, we review the functions of myosins associated with hearing loss and also describe pathogenic and likely pathogenic variants documented in ClinVar and discuss correlations between variants and hearing loss.
3 Myosins and hearing loss
3.1 Loci and variants
As summarized in Table 1, two genes encoding conventional myosins, MYH9 and MYH14, and four genes encoding unconventional myosins, MYO3A, MYO6, MYO7A and MYO15A, are associated with nonsyndromic hereditary hearing loss in human. The kinetic properties and functions of these myosins are different from one another. MYO3A and MYO15A are currently identified as loci of autosomal recessive nonsyndromic hearing loss, DFNB30 and DFNB3, respectively (Wang et al., 1998; Walsh et al., 2002). MYH9 and MYH14 are identified as chromosomal loci of autosomal dominant nonsyndromic hearing loss, DFNA17 and DFNA4A, respectively (; Wang et al., 2000; ). The other two myosin genes, MYO6 and MYO7A, depending on the variants, are associated with both autosomal dominant and recessive nonsyndromic hearing loss, respectively, as DFNA22 and DFNB37 for MYO6 (; ) and DFNA11 and DFNB2 for MYO7A (; Weil et al., 1997). Some variants of MYO7A are associated with Usher syndrome type 1. The locus is designated USH1B (Weil et al., 1995). Variants of these genes are available in databases such as ClinVar, Deafness Variation Database and gnomAD.
Correlation between variants of these myosin genes and clinical phenotypes is crucial for hearing researchers to (1) elucidate the pathophysiology of hearing loss, (2) predict the outcome of a given variant in a patient and (3) formulate therapeutic strategies for hearing loss. For clinicians, it would be best if the audiological prognosis is predictable including thresholds at each frequency in the pure tone audiogram, speech discrimination, time course in loss of hearing ability, mode of inheritance and penetrance. AlphaMissense () provides in silico predictions for missense variants. It is also imperative to include experimental data on how each variant alters the structure or kinetics of a myosin and results in hearing loss in animal models. However, it is challenging to predict if a variant that slightly modifies the kinetics of a protein (e.g., the ATPase activity of the motor domain) will be pathogenic or not. These changes in kinetics may cause hearing loss later in life or be pathogenic only for a person with other risk alleles in their genetic background. Correlation analyses between variants and clinical outcomes may some day be complemented by aggregating environmental hazards and risks and safeguards in a patient’s genetic background. Correlations between variants of myosin genes and clinical phenotypes have been reported in several studies (Tamagawa et al., 2002; Riazuddin et al., 2008; Rehman et al., 2016; ). We have summarized these observations by mapping pathogenic or likely pathogenic variants available in ClinVar to the domain structures of all the myosins currently associated with human hearing loss (Figure 3B; Figure 4; Figure 5C; Figure 6C; Figure 7). In the subsections below, we examine the functions and structures of myosins necessary for normal hearing, raise questions about protein trafficking in stereocilia and further discuss the spectrum of variants in these myosin genes associated with hearing loss.
FIGURE 4
FIGURE 5
FIGURE 6
FIGURE 7
3.2 MYO3A
MYO3A has a 30-kDa kinase domain at the N-terminus and a tail that can interact with MORN4, isoform 1 of ESPN and F-actin (Figure 3A). The N-terminal kinase domain can phosphorylate two residues in the “loop 2” of the motor domain connecting the upper and lower 50-kDa domains and reduce the maximum actin-activated ATPase activity (kcat) and affinity for F-actin (Quintero et al., 2010). This phosphorylation may auto-regulate the MYO3A motor activity in F-actin protrusions, such as filopodia and stereocilia (Quintero et al., 2010). The kinase domain itself has two threonine residues that can be phosphorylated, of which the C-terminal threonine has a larger impact on the kinase activity (Quintero et al., 2013). Phosphorylation of the C-terminal threonine residue in the kinase domain is mediated by another MYO3A molecule or cellular kinases, likely increasing the activity of the MYO3A kinase domain (Quintero et al., 2013). This myosin was initially considered to have a high duty ratio (∼0.9) with fast phosphate release and slow ADP release (). However, more recent analyses indicate that MYO3A has a low duty ratio (0.25) after removing the kinase domain, which enhances the ATPase activity by two-fold ().
The MYO3A tail domain is partially unfolded but has region/domains that interact with MORN4, THDI (tail homology domain I) and THDII (tail homology domain II). MORN4 can tether its interacting partners to the plasma membrane (). THDI and THDII interact with the Ankyrin (ANK) repeat of ESPN isoform 1 or ESPNL and directly with F-actin, respectively (; Salles et al., 2009; ). Co-expression of human MYO3A lacking the kinase domain and mouse ESPN isoform 1 fragments in COS-7 cells showed elongated filopodia suggesting that constitutively active MYO3A (without regulation by the kinase domain) may recruit ESPN isoform 1 to stereocilia and boost elongation of F-actin cores (Salles et al., 2009). Concordantly, the ESPN isoform 1 knockout mouse and the jerker mouse show short, thin, immature stereocilia (Sekerkova et al., 2011; ). However, a MYO3A without the kinase domain is not reported to be present in stereocilia. How the kinase domain regulates MYO3A function in stereocilia elongation, and if MYO3A with the kinase domain might be a processive motor remain to be elucidated. Interestingly, in mice, the loss of function of MYO3A is likely compensated by MYO3B. Myo3a−/− mice have normal hearing at 1 month of age while a double knockout of Myo3a and Myo3b results in profound deafness and a dysmorphic staircase architecture of hair cell stereocilia bundles ().
In humans, variants of MYO3A are associated with autosomal recessive nonsyndromic hearing loss, DFNB30 (Walsh et al., 2002). ClinVar aggregates different types of variants in this gene and associates them with autosomal recessive hearing loss or hearing loss with no description of mode of inheritance (AR and HL in Figure 3B). Most variants of MYO3A are nonsense mutations, frameshift mutations or mutations in the non-coding region and located in the kinase domain, the motor domain or the neck region (Figure 3B, yellow rectangle). These variants likely disrupt motor function by inserting a premature stop codon or by causing a shift in the reading frame (frameshift) of the mature mRNA. Two frameshift variants are reported in the THDI domain, which may disable the recruitment of ESPN isoform 1 or ESPNL to stereocilia (Figure 3B, arrowheads). Three missense mutations in the kinase domain (p.Leu239Pro) and in the motor domain (p.Gly488Glu and p. Leu697Trp) are each associated with autosomal dominant hearing loss (; ; ) (AD in Figure 3B). Although the precise mechanism of the dominant inheritance is unknown, biochemical experiments show that the two mutations in the motor domain lower the ATPase activity and alter its velocity in an F-actin sliding assay (increased by p. Gly488Glu; decreased by p. Leu697Trp) (; ).
A remaining question is how MYO3A traffics in a stereocilium. Currently, there is no evidence that MYO3A has a dimerization sequence, such as a coiled-coil domain, to “walk” on F-actin as a dimer or an oligomer (). The low duty ratio (∼0.25) of the motor domain in the absence of the kinase domain contradicts processive walking (). To move in filopodia and stereocilia, MYO3A requires interaction with F-actin through THDII in order to perhaps cause “inchworm-like” movements (Salles et al., 2009; Raval et al., 2016). ESPN isoform 1 (or ESPNL) may assist MYO3A to move in actin protrusions considering that the tail of MYO3B, which lacks THDII to interact with F-actin, can target filopodia tips only when co-expressed with ESPN isoform 1 (). Increase of the duty ratio by the kinase domain could be advantageous for MYO3A to move on F-actin using its THDII domain or its cargo, ESPN isoform 1, as a scaffold although the phosphorylated motor domain also decreases its affinity for F-actin (; ). It is still uncertain how class-III myosins move in F-actin protrusions including stereocilia.
3.3 MYO6
All but one myosin studied to date move on F-actin toward the barbed end. The exception is MYO6, which moves toward the pointed end of F-actin. MYO6 has an insertion called the “reverse gear” located between the converter domain and the lever arm (Wells et al., 1999; Shin et al., 2004) that is necessary for movement to the pointed end of F-actin. MYO6 also has a unique tail consisting of a single 26-kDa globular cargo binding domain (CBD) with multiple motifs to interact with a wide variety of binding partners involved in autophagy (TAX1BP, OPTN and NDP52), endocytosis (Dab2, LMTK2, TOM1/L2), mitophagy (Ubiquitin) and G-protein signaling (GIPC) () (Figure 2E). These proteins localize on the cytoplasmic side of vesicles or membrane pits, including those involved in endocytosis, and are considered to tether MYO6A to these structures (). It is also known that MYO6 can directly interact with PIP2 in the plasma membrane through its C-terminal lipid-binding motif (Spudich et al., 2007). Some of these interacting partners, such as Dab2, OPTN and GIPC, can dimerize or oligomerize MYO6 (Phichith et al., 2009; Yu et al., 2009; Shang et al., 2017; ). Despite these advances in understanding MYO6 function, MYO6 functions in the inner ear, especially in hair cells, is not fully understood. Loss of MYO6 function in Snell’s waltzer mice (Myo6sv/sv) results in profound hearing loss accompanying fusion of adjacent stereocilia and subsequent degeneration of the organ of Corti (). Bifurcated stereocilia often observed in this mouse line suggest that MYO6 anchors the plasma membrane to the F-actin core (Self et al., 1999). MYO6 also interacts with tyrosine phosphatase receptor type Q (PTPRQ), a membrane protein crucial to tether the plasma membrane to the F-actin stereocilia core (; ; Sakaguchi et al., 2008). Furthermore, it is uncertain if MYO6 loaded with cargo traffics in a stereocilium. MYO6 ceases stepping and behaves as a molecular anchor rather than a molecular transporter when (1) under load and (2) at subsaturated ATP or in the presence of ADP (). MYO6 may anchor stereocilia rootlets to the hair cell apical plasma membrane through PTPRQ, exerting force to help keep each stereocilium in place ().
Both autosomal dominant DFNA22 and recessive nonsyndromic hearing loss DFNB37 deafness are associated with variants of MYO6 (; ). Most variants of MYO6 affect the motor domain and the neck region (Figure 4, yellow rectangle) except for some frameshift variants in the CBD (Figure 4, arrowheads). Unfortunately, many variants of MYO6 are reported in ClinVar without information about the mode of inheritance (Figure 4). However, heterozygous Myo6+/sv and Myo6+/− mice suggest that haploinsufficiency of MYO6 function in the inner ear explains the progressive hearing loss (; Seki et al., 2021). A frameshift mutation at the N-terminus (p.Thr13fs), located in annotated exon 1 of MYO6, is associated with autosomal recessive hearing loss, DFNB37 (Figure 4, arrow). For this variant, perhaps the MYO6 transcript may be translated from the methionine codon at nucleotide position 18 (NM016239.4) or further downstream. A second possibility is alternative splicing that includes a “hidden” 1st exon located in highly conserved sequence in intron 1 but which in a homozygous p. Thr13fs individual is insufficient in producing enough functional MYO6 for a normal phenotype. A missense variant (p.Glu299Asp) in the motor domain is associated with autosomal recessive hearing loss, which may be the result of a slightly hypofunctional motor domain whose activity is insufficient when homozygous but sufficient when heterozygous (Figure 4, open arrowhead).
3.4 MYO7A
MYO7A has a long tail domain of approximately 1,200 residues consisting of two MyTH4-FERM domains and one SH3 domain (Figure 2E). MYO7A localizes at the upper tip-link density (UTLD) with other components of the tip-link complex, USH1C (harmonin), SANS and CDH23 (), and tethers PCDH15 at the tip of an adjacent shorter stereocilium () (Figure 1D). PCDH15 is mechanically connected to the MET channel complex composed of TMC1/TMC2 and accessory proteins, TMIE, CIB2 and probably LOXHD1 (Naz et al., 2002; Zhao et al., 2014; ; ; Trouillet et al., 2021). Genes encoding the components of the tip-link complex and the MET channel complex, USH1C, CDH23, PCDH15, TMIE and CIB2, are associated with autosomal recessive nonsyndromic hearing loss, DFNB18, DFNB12, DFNB23, DFNB6 and DFNB48, respectively (; Naz et al., 2002; ; Riazuddin et al., 2012). Some components of the tip-link complex are also utilized in photoreceptors (). In addition to MYO7A, four genes encoding the tip-link complex, USH1C, SANS, CDH23 and PCDH15, are associated with Usher syndrome type 1 (Verpy et al., 2000; ; ; ; Weil et al., 2003). MYO7A is also involved in transporting twinfilin-2 to stereocilia tips (Rzadzinska et al., 2009) and formation of the ankle link through interaction with a scaffolding protein PDZD7 (; Morgan et al., 2016).
MYO7A and their interacting partners are essential components of the tip-link complex. Recent studies have elucidated an interactome among MYO7A and cargo (Figure 5A). Mouse models disabling or partially disabling the tip-link components have been useful tools to understand the formation of the tip-link complex. For example, localization of harmonin B at the UTLD is lost in mice with defective MYO7A (Myo7a4626SB/4626SB) or SANS (Ush1gjs/js) but retained in mice with mutant CDH23 (Cdh23v2J/v2J) or PCDH15 (Pcdh15av3J/av3J) () suggesting that localization of harmonin B is dependent on MYO7A and SANS. The F-actin binding motif of harmonin B is essential for forming the UTLD and anchoring the tip-link to the F-actin core but not necessary for transporting the tip-link complex and harmonin B itself (). The eleven amino-acid extension of the canonical isoform of MYO7A (MYO7A-C in Figure 5B) may be crucial for maintaining the tip-link complex because mice lacking the MYO7A-C isoform show reduced resting open probability and slowed onset of MET currents and progressive hearing loss (). The tip-link components are likely replenished continuously because postnatal deletion of Ush1c and Ush1g alleles show progressive loss of tip-links and the corresponding mutant mice are profoundly deaf (). Interestingly, postnatal deletion of Myo7a shows progressive hearing loss and results in profound deafness in mice around P60 accompanying a decrease in MET currents without the loss of tip-links (). Once tip-links are formed, the motor activity of MYO7A is probably not required to replenish their components.
Compared with its binding partners, less is known about how the motor activity of MYO7A is utilized in a stereocilium. Proteins in the interactome of MYO7A may provide several mechanisms for MYO7A to move in a stereocilium, (1) dimerization, (2) anchoring to the plasma membrane via CDH23 or PCDH15 (; ) and (3) binding to F-actin via harmonin B () (Figure 5A). For dimerization, the SAH domain of MYO7A likely has a weak dimerization activity considering that a small portion of Drosophila myosin VIIa fragment (head + neck) can spontaneously dimerize and walk on F-actin () and that the SAH domain contains a motif resembling a leucine zipper (Sakai et al., 2011). In addition, SANS, PCDH15 and CDH23 can dimerize with each other and may keep multiple MYO7A molecules in close proximity (; ; ). Two other mechanisms may be utilized by MYO10 and MYO3A to move in F-actin protrusions. Anchoring to the plasma membrane can be used by MYO10 to form F-actin protrusions at the cell edge and then move toward the tip in the protrusion (). Binding to F-actin is necessary for MYO3A to move in a stereocilium or a filopodium (Salles et al., 2009; Raval et al., 2016). An open question is why MYO7A shows slow movements as a dimer, especially when compared with MYO10, which is a motor with high duty ratio functioning in filopodia (Takagi et al., 2014). MYO7A and MYO10 show similar velocities in the F-actin sliding assay, 0.19 μm/s and 0.17 μm/s, respectively (; Watanabe et al., 2006). However, these two myosins show different kinetics in single-molecule microscopy experiments using homodimers. Dimerized human MYO7A can only move at 11.0 ± 0.6 nm/s (Sato et al., 2017), while dimerized MYO10 can move at 578 ± 174 nm/s in filopodia (). Interestingly, movements of human MYO7A are slower than Drosophila myosin VIIa (crinkled), 72 ± 20 nm/s (Sato et al., 2017). The slow movements of MYO7A might prevent this motor protein from behaving like MYO10, which makes cellular protrusions when anchored to the plasma membrane ().
Variants of MYO7A are associated with hearing loss and/or retinal pathology (Figure 5C). Nonsense and frameshift variants in MYO7A usually result in autosomal recessive Usher syndrome type 1 or nonsyndromic hearing loss (yellow rectangles, Figure 5C). However, some nonsense and frameshift variants are also associated with autosomal dominant nonsyndromic hearing loss (pink rectangle, Figure 5C, plotted by crosses to indicate association with multiple phenotypes). Similar overlaps are observed in missense mutations (open and closed arrowheads, Figure 5C). Furthermore, 27 variants can cause only retinal symptoms (VIS in Figure 5C). Variable expressivity of MYO7A, and perhaps genes related to MYO7A, may be a reason why one variant can show different phenotypes (Zina et al., 2001). Correlation between genotypes and phenotypes, such as onset and severity of hearing loss and presence of retinal dysfunction, is complex. Currently, it is still challenging to correlate genotypes and phenotypes in Usher syndrome (). Missense variants are reported in the first methionine of the N-terminal extension (p.Met1Val and p. Met1Ile) and are associated with Usher syndrome and autosomal recessive hearing loss (arrows in Figure 5C) suggesting the importance of this extension in human for intact functions of the retina and stereocilia.
3.5 MYO15A
The domain structure of the MYO15A tail is similar to MYO7A. Both have two MyTH4-FERM domains and one SH3 domain (Figure 2E). One large difference from MYO7A is a 133-kDa N-terminal domain encoded by exon 2 of MYO15A (Figure 6B). Formerly, two isoforms with and without this N-terminal extension were found and referred to as MYO15A-L and MYO15A-S. Recently, a third isoform with a small 6-kDa N-terminal extension was identified in cochlear hair cells (Rehman et al., 2016; Ranum et al., 2019) renaming the three isoforms as MYO15A-1, MYO15A-2 and MYO15A-3, respectively (Figure 6B). MYO15A-1 is localized at the tips of short stereocilia near PCDH15 and is essential for maintaining the length of the mechanotransducing stereocilia (). MYO15A-2 lacking the N-terminal domain is crucial for elongating stereocilia to a developmentally predetermined length and can rescue abnormally short stereocilia in Shaker-2 mice (). Although the exact function of MYO15A-3 is unknown, a previous review points to its involvement in trafficking of BAIAP2L2 (Moreland and Bird, 2022), which is an inverse BAR (I-BAR) domain proteins and interacts with phosphoinositide-rich membrane to induce plasma membrane protrusions (Zhao et al., 2011). The C-terminal PDZ ligand of MYO15A interacts with a scaffolding protein whirlin (), and MyTH4-FERM domain with an F-actin interacting protein EPS8 (Manor et al., 2011) (Figure 6A). The ternary complex of MYO15A, whirlin (WHRN) and EPS8 is essential for elongating the F-actin core. The shaker-2, whirler and Eps8−/− mice fail to elongate stereocilia to a wild-type length (; Mogensen et al., 2007; Zampini et al., 2011). MYO15A also has the ability to nucleate F-actin, which may contribute to the elongation of the F-actin core (Moreland et al., 2021). The ternary complex of WHRN, GPSM2 and GNAI3 is also part of the MYO15A interactome. WHRN specifies the tallest stereocilia and defines hair bundle row identity (Tadenev et al., 2019). It is unknown how MYO15A traffics in a stereocilia, but the relatively high duty ratio of its motor domain (∼0.5) is consistent with processive movements as a dimer or an oligomer ().
Currently, variants of MYO15A are associated with autosomal recessive nonsyndromic hearing loss DFNB3 (Figure 6C). In addition to the nonsense and frameshift mutations distributed along the entire length of MYO15A and missense mutations in the motor domain, some missense variants are observed in the large N-terminal domain indicating the importance of this sequence (yellow rectangle with asterisk, Figure 6C). One variant truncates the C-terminal PDZ ligand as previously reported (Rehman et al., 2016) (arrowhead, Figure 6C). Interestingly, some missense mutations are reported in the first MyTH4-FERM domain and in the SH3 domain suggesting that these tail domains are sites of yet to be identified binding partners (yellow rectangle with double asterisks, Figure 6C).
3.6 Non-muscle class II myosins
Currently, variants of MYH9 and MYH14 genes are associated with autosomal dominant nonsyndromic hearing loss, DFNA17 and DFNA4A, respectively (; Wang et al., 2000; ). Class-II myosins contain three non-muscle myosins, NMIIA (MYH9), NMIIB (MYH10) and NMIIC (MYH14) (). Non-muscle class-II myosins are present in every cell type (). They form contractile actomyosin structures essential for cellular organization, polarity and regulation (Vicente-Manzanares et al., 2009) (Figure 2D). Expression of non-muscle myosins are different among cell types. NMIIA and NMIIB are expressed in endothelial and epithelial cells at similar levels while NMIIB and NMIIC are abundant in nervous and lung tissue, respectively (; ). NMIIA, NMIIB and NMIIC are expressed in mammalian cochlear epithelia and regulate extension, growth and patterning of the cochlear duct (Yamamoto et al., 2009).
The distribution of MYH9 and MYH14 variants are unique compared with variants of unconventional myosins (Figure 7). Nonsense or frameshift variants are only found close to the N-terminus or the C-terminus probably suggesting a dominant negative effect of truncated proteins (arrows in Figure 7). While almost all MYH14 variants are associated with autosomal dominant hearing loss, most variants of MYH9 are associated with other MYH9-related disorders including platelet disorders and nephritis () (MYH9-REL in Figure 7A). Among the variants associated with MYH9-related disorders, there is one cluster of inframe mutations (p.Gln1068_Leu1074dup, p. Gln1068_Leu1074del and p. Glu1084del) in the coiled-coil domain that probably does not have a destructive effect on protein folding (open arrow in Figure 7A). One variant is associated with a pleiotropic phenotype including an abnormality of platelets and facial dysmorphology (p.Asp1424Gly, arrowhead in Figure 7A). All missense variants associated with autosomal dominant hearing loss occur in the motor domain close to the neck, in the neck or in the tail and are also associated with MYH9-related disorders (yellow rectangle in Figure 7A and plotted by crosses to indicate association with multiple phenotypes). In patients with these variants, platelet disorders might be overlooked because of (1) bleeding is more frequently associated with variants in the motor domain than variants in the neck and the tail and (2) a tendency toward bleeding (e.g., easy bruising, epistaxis and gum bleeding) can manifest differently even between a parent and a child harboring the same variant of MYH9 (Saposnik et al., 2014).
3.7 Disputed or refuted “deafness genes”: MYO1A, MYO1C and MYO1F
To date, three genes encoding the class-I myosins, MYO1A, MYO1C and MYO1F, were initially reported as human “deafness genes” (; Zadro et al., 2009). Association of variants of MYO1A with deafness was refuted as either the variants of MYO1A were identified in healthy controls or the deafness was explained by convincing variants of different genes (; Patton et al., 2016). Absence of any overt pathology in homozygous Myo1a knockout mice supports these findings (Tyska et al., 2005). Association of MYO1C and MYO1F variants with deafness was disputed by the ClinGen Hearing Loss Clinical Domain Working Group (CDWG) due to a lack of sufficient functional analyses (). This class of myosins have a neck containing three IQ motifs and a tail with a tail homology 1 (TH1) domain (MYO1A–D, G and H) or two tail homology domains (TH1 and TH2) and one SH3 domain (MYO1E and F) () (Figure 2E). The TH1 domain has a putative pleckstrin homology (PH) motif and can interact with PIP2 in the lipid bilayer (). In the inner ear, MYO1C was reported to be involved in adaptation of MET channels (i.e., rapid closing of activated MET channels) through interaction with the plasma membrane (Stauffer et al., 2005). Future studies may find additional association of class-I myosins with inner ear function.
4 Discussion
Genetic studies have identified more than one hundred genes with variants associated with hearing loss including four genes encoding unconventional myosins, MYO3A, MYO6, MYO7A and MYO15A, and two genes encoding conventional myosins, MYH9 and MYH14. The four unconventional myosins and some class-I myosins are expressed in hair cells and are essential for developing and maintaining functional stereocilia. The tail domains of these unconventional myosins have motifs unique for each protein and have evolved to interact with specific protein partners and phospholipids (PIP2), which are often referred to as “cargo” transported and/or anchored on the F-actin core of a stereocilium. Major functions of cargo proteins can be largely categorized into (1) formation of the MET machinery, (2) elongation of the F-actin core and (3) tethering the plasma membrane and certain links to the F-actin core (Figure 1D) but not limited to these. For example, Twinfilin-2, which caps F-actin of stereocilia in shorter rows, is identified as cargo of MYO7A (Rzadzinska et al., 2009). In addition to elucidating the functions of cargo proteins in stereocilia development, recent topics include novel isoforms of MYO7A and MYO15A derived from previously “hidden” alternatively spliced small exons (Rehman et al., 2016; Ranum et al., 2019; ).
Compared with the interacting partners of these myosins, less is understood about how the motor activities of these myosins are utilized and regulated in a stereocilium. For example, it is unknown how MYO7A becomes localized at the UTLD and whether or not it is dimerized. In the retina, MYO7A can be recruited to melanosomes by MYRIP which activates the MYO7A motor function through cargo-mediated dimerization (; Sakai et al., 2011). However, there is no evidence that MYRIP is utilized in hair cell stereocilia although it is present. RNAseq in FACS-sorted hair cells shows higher expression of MYRIP in supporting cells than in hair cells (https://shield.hms.harvard.edu/viewgene.html?gene=Myrip). One scenario is that proteins in the MYO7A interactome provide mechanisms for MYO7A to move in a stereocilium as discussed in the previous section. Another possibility is that MYO7A is directly recruited to the UTLD by the proteins already there, such as CDH23, harmonin B and SANS, although another mechanism would be necessary to recruit these proteins to the UTLD in this scenario. A similar challenge can be posed to other myosins, such as MYO6 and MYO15A, for which the entire interactome in hair cells needs to be clarified. Utilization of motor activities in stereocilia may be difficult to analyze using conventional mouse models lacking functional myosins or their cargo because stereocilia in these mouse models are often severely deformed, disturbing the cargo transport system in them (). To approach utilization and regulation of motor activities in a stereocilium, advances in single molecule visualization methodologies will be required to observe the in vivo behaviors of myosins and cargo in real time in live hair cell stereocilia.
In addition, we speculate that more detailed clinical information of patients is necessary for correlation analyses between variants and phenotypes. Large databases, such as ClinVar and gnomAD, aggregate variants with clinical symptoms. However, even from these carefully curated databases, it is difficult to obtain detailed measurements necessary for hearing research, such as thresholds at each frequency in the pure tone audiograms, speech discrimination, time course in loss of hearing ability and the clinical conditions of patients including accompanying symptoms, because these details are written in a format different for each journal, database and website. From a technical point of view, more flexible approaches, such as artificial intelligence and machine learning, may be useful to handle large and often unformatted data. Artificial intelligence has already been introduced into clinical genomics laboratories and utilized to predict the pathogenicity and phenotypic consequence of variants (). With the ability to handle large data, these novel tools may assist hearing researchers to discover correlations between variants and phenotypes and to identify variants of high priority.
Active transport by myosins are crucial for developing cell protrusions including stereocilia, microvilli and filopodia (). Elucidating the pathophysiology of hearing loss caused by myosin variants will be useful to formulate therapeutic strategies not only for sensorineural hearing loss but also for other diseases such as cancer, virus infection and inflammatory bowel diseases.
Statements
Author contributions
TM: Conceptualization, Funding acquisition, Methodology, Project administration, Software, Validation, Visualization, Writing–original draft, Writing–review and editing. IB: Validation, Visualization, Writing–review and editing. MS: Validation, Writing–review and editing. TF: Funding acquisition, Project administration, Validation, Writing–review and editing, Supervision.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. TM, IB, and TF were supported, in part, by NIDCD intramural research funds DC000039 to TF. TM and MS were also supported by the start-up fund from Southern Illinois University School of Medicine and the K99/R00 Pathway-to-Independence Award to TM (1K99DC019949 and 4R00DC019949).
Acknowledgments
We thank Drs. Dennis Winkler and Mhamed Grati for valuable comments and Ms. Erina He for her beautiful diagrams. Raw data and Python scripts used to draw graphs in Figures 3B, 4, 5C, 6C and 7 are available at the first author’s GitHub repository (https://github.com/takushim/fpvariants).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
ATP, adenosine triphosphate; ADP, adenosine diphosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; DFNA, chromosomal locus for dominantly inherited nonsyndromic deafness; DFNB, chromosomal locus for recessively inherited nonsyndromic deafness; ELC, essential light chain; RLC, regulatory light chain; CaM, calmodulin; IQ-motif, isoleucine-glutamine-rich motif, USH, Usher syndrome; OHC, outer hair cell; IHC, inner hair cell; RT, room temperature.
References
1
AdatoA.MichelV.KikkawaY.ReinersJ.AlagramamK. N.WeilD.et al (2005). Interactions in the network of Usher syndrome type 1 proteins. Hum. Mol. Genet.14, 347–356. 10.1093/hmg/ddi031
2
AhmedZ. M.MorellR. J.RiazuddinS.GropmanA.ShaukatS.AhmadM. M.et al (2003a). Mutations of MYO6 are associated with recessive deafness, DFNB37. Am. J. Hum. Genet.72, 1315–1322. 10.1086/375122
3
AhmedZ. M.RiazuddinS.AhmadJ.BernsteinS. L.GuoY.SabarM. F.et al (2003b). PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum. Mol. Genet.12, 3215–3223. 10.1093/hmg/ddg358
4
AhmedZ. M.RiazuddinS.BernsteinS. L.AhmedZ.KhanS.GriffithA. J.et al (2001). Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet.69, 25–34. 10.1086/321277
5
AlagramamK. N.YuanH.KuehnM. H.MurciaC. L.WayneS.SrisailpathyC. R.et al (2001). Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum. Mol. Genet.10, 1709–1718. 10.1093/hmg/10.16.1709
6
AlthausK.GreinacherA. (2009). MYH9-related platelet disorders. Semin. Thromb. Hemost.35, 189–203. 10.1055/s-0029-1220327
7
AltmanD.SweeneyH. L.SpudichJ. A. (2004). The mechanism of myosin VI translocation and its load-induced anchoring. Cell116, 737–749. 10.1016/s0092-8674(04)00211-9
8
AnnaA.MonikaG. (2018). Splicing mutations in human genetic disorders: examples, detection, and confirmation. J. Appl. Genet.59, 253–268. 10.1007/s13353-018-0444-7
9
AradhyaS.FacioF. M.MetzH.MandersT.ColavinA.KobayashiY.et al (2023). Applications of artificial intelligence in clinical laboratory genomics. Am. J. Med. Genet. C Semin. Med. Genet.193, e32057. 10.1002/ajmg.c.32057
10
AvrahamK. B.HassonT.SobeT.BalsaraB.TestaJ. R.SkvorakA. B.et al (1997). Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice. Hum. Mol. Genet.6, 1225–1231. 10.1093/hmg/6.8.1225
11
AvrahamK. B.HassonT.SteelK. P.KingsleyD. M.RussellL. B.MoosekerM. S.et al (1995). The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nat. Genet.11, 369–375. 10.1038/ng1295-369
12
BagshawC. R.TrenthamD. R. (1974). The characterization of myosin-product complexes and of product-release steps during the magnesium ion-dependent adenosine triphosphatase reaction. Biochem. J.141, 331–349. 10.1042/bj1410331
13
BahlerM.RhoadsA. (2002). Calmodulin signaling via the IQ motif. FEBS Lett.513, 107–113. 10.1016/s0014-5793(01)03239-2
14
BattersC.VeigelC. (2016). Mechanics and activation of unconventional myosins. Traffic17, 860–871. 10.1111/tra.12400
15
BelyantsevaI. A.BogerE. T.FriedmanT. B. (2003). Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle. Proc. Natl. Acad. Sci. U. S. A.100, 13958–13963. 10.1073/pnas.2334417100
16
BelyantsevaI. A.BogerE. T.NazS.FrolenkovG. I.SellersJ. R.AhmedZ. M.et al (2005). Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat. Cell Biol.7, 148–156. 10.1038/ncb1219
17
BeyerL. A.OdehH.ProbstF. J.LambertE. H.DolanD. F.CamperS. A.et al (2000). Hair cells in the inner ear of the pirouette and shaker 2 mutant mice. J. Neurocytol.29, 227–240. 10.1023/a:1026515619443
18
BirdJ. E.TakagiY.BillingtonN.StrubM. P.SellersJ. R.FriedmanT. B. (2014). Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking. Proc. Natl. Acad. Sci. U. S. A.111, 12390–12395. 10.1073/pnas.1409459111
19
BolzH.Von BrederlowB.RamirezA.BrydaE. C.KutscheK.NothwangH. G.et al (2001). Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat. Genet.27, 108–112. 10.1038/83667
20
BorkJ. M.PetersL. M.RiazuddinS.BernsteinS. L.AhmedZ. M.NessS. L.et al (2001). Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am. J. Hum. Genet.68, 26–37. 10.1086/316954
21
BritoC.SousaS. (2020). Non-muscle myosin 2A (NM2A): structure, regulation and function. Cells9, 1590. 10.3390/cells9071590
22
BussF.Kendrick-JonesJ. (2008). How are the cellular functions of myosin VI regulated within the cell?Biochem. Biophys. Res. Commun.369, 165–175. 10.1016/j.bbrc.2007.11.150
23
CaberlottoE.MichelV.FoucherI.BahloulA.GoodyearR. J.PepermansE.et al (2011). Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia. Proc. Natl. Acad. Sci. U. S. A.108, 5825–5830. 10.1073/pnas.1017114108
24
ChantlerP. D.WylieS. R.Wheeler-JonesC. P.McgonnellI. M. (2010). Conventional myosins - unconventional functions. Biophys. Rev.2, 67–82. 10.1007/s12551-010-0030-7
25
ChatterjeeP.MorganC. P.KreyJ. F.BensonC.GoldsmithJ.BateschellM.et al (2023). GIPC3 couples to MYO6 and PDZ domain proteins, and shapes the hair cell apical region. J. Cell Sci.136, jcs261100. 10.1242/jcs.261100
26
CheneyR. E.MoosekerM. S. (1992). Unconventional myosins. Curr. Opin. Cell Biol.4, 27–35. 10.1016/0955-0674(92)90055-h
27
ChengJ.NovatiG.PanJ.BycroftC.ZemgulyteA.ApplebaumT.et al (2023). Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science381, eadg7492. 10.1126/science.adg7492
28
CiriloJ. A.Jr.GuntherL. K.YengoC. M. (2021). Functional role of class III myosins in hair cells. Front. Cell Dev. Biol.9, 643856. 10.3389/fcell.2021.643856
29
CollinsK.SellersJ. R.MatsudairaP. (1990). Calmodulin dissociation regulates brush border myosin I (110-kD-calmodulin) mechanochemical activity in vitro. J. Cell Biol.110, 1137–1147. 10.1083/jcb.110.4.1137
30
ColuccioL. M. (2020). “Myosins and disease,” in Myosins: a superfamily of molecular motors. Editor ColuccioL. M. (Cham: Springer International Publishing), 245–316.
31
CoreyD. P.HudspethA. J. (1979). Ionic basis of the receptor potential in a vertebrate hair cell. Nature281, 675–677. 10.1038/281675a0
32
CoreyD. P.HudspethA. J. (1983). Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci.3, 962–976. 10.1523/JNEUROSCI.03-05-00962.1983
33
CornsL. F.JohnsonS. L.RobertsT.RanatungaK. M.HendryA.CerianiF.et al (2018). Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation. Nat. Commun.9, 4015. 10.1038/s41467-018-06307-w
34
CosgroveD.ZallocchiM. (2014). Usher protein functions in hair cells and photoreceptors. Int. J. Biochem. Cell Biol.46, 80–89. 10.1016/j.biocel.2013.11.001
35
CostaA. R.SousaM. M. (2020). Non-muscle myosin II in axonal cell biology: from the growth cone to the axon initial segment. Cells9, 1961. 10.3390/cells9091961
36
CraigR.WoodheadJ. L. (2006). Structure and function of myosin filaments. Curr. Opin. Struct. Biol.16, 204–212. 10.1016/j.sbi.2006.03.006
37
CramerL. P. (2000). Myosin VI: roles for a minus end-directed actin motor in cells. J. Cell Biol.150, F121–F126. 10.1083/jcb.150.6.f121
38
DantasV. G. L.RavalM. H.BallesterosA.CuiR.GuntherL. K.YamamotoG. L.et al (2018). Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss. Sci. Rep.8, 8706. 10.1038/s41598-018-26818-2
39
De JongeJ. J.BattersC.O'loughlinT.ArdenS. D.BussF. (2019). The MYO6 interactome: selective motor-cargo complexes for diverse cellular processes. FEBS Lett.593, 1494–1507. 10.1002/1873-3468.13486
40
De La CruzE. M.OstapE. M. (2004). Relating biochemistry and function in the myosin superfamily. Curr. Opin. Cell Biol.16, 61–67. 10.1016/j.ceb.2003.11.011
41
De La CruzE. M.OstapE. M.SweeneyH. L. (2001). Kinetic mechanism and regulation of myosin VI. J. Biol. Chem.276, 32373–32381. 10.1074/jbc.M104136200
42
De La CruzE. M.WellsA. L.RosenfeldS. S.OstapE. M.SweeneyH. L. (1999). The kinetic mechanism of myosin V. Proc. Natl. Acad. Sci. U. S. A.96, 13726–13731. 10.1073/pnas.96.24.13726
43
Diaz-ValenciaJ. D.Estrada-AbreoL. A.Rodriguez-CruzL.Salgado-AguayoA. R.Patino-LopezG. (2022). Class I Myosins, molecular motors involved in cell migration and cancer. Cell Adh Migr.16, 1–12. 10.1080/19336918.2021.2020705
44
DionneG.QiuX.RappM.LiangX.ZhaoB.PengG.et al (2018). Mechanotransduction by PCDH15 relies on a novel cis-dimeric architecture. Neuron99, 480–492. 10.1016/j.neuron.2018.07.006
45
DistefanoM. T.HemphillS. E.OzaA. M.SiegertR. K.GrantA. R.HughesM. Y.et al (2019). ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs. Genet. Med.21, 2239–2247. 10.1038/s41436-019-0487-0
46
DollJ.HofrichterM. a.H.BahenaP.HeihoffA.SegebarthD.MullerT.et al (2020). A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family. Mol. Genet. Genomic Med.8, e1343. 10.1002/mgg3.1343
47
DominguezR.FreyzonY.TrybusK. M.CohenC. (1998). Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: visualization of the pre-power stroke state. Cell94, 559–571. 10.1016/s0092-8674(00)81598-6
48
DonaudyF.FerraraA.EspositoL.HertzanoR.Ben-DavidO.BellR. E.et al (2003). Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am. J. Hum. Genet.72, 1571–1577. 10.1086/375654
49
DonaudyF.SnoeckxR.PfisterM.ZennerH. P.BlinN.Di StazioM.et al (2004). Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am. J. Hum. Genet.74, 770–776. 10.1086/383285
50
DoseA. C.AnanthanarayananS.MooreJ. E.BurnsideB.YengoC. M. (2007). Kinetic mechanism of human myosin IIIA. J. Biol. Chem.282, 216–231. 10.1074/jbc.M605964200
51
DoseA. C.AnanthanarayananS.MooreJ. E.CorsaA. C.BurnsideB.YengoC. M. (2008). The kinase domain alters the kinetic properties of the myosin IIIA motor. Biochemistry47, 2485–2496. 10.1021/bi7021574
52
EatockR. A.LysakowskiA. (2006). “Mammalian vestibular hair cells,” in Vertebrate hair cells. Editors EatockR. A.FayR. R.PopperA. N. (New York, NY: Springer New York), 348–442.
53
EbrahimS.AvenariusM. R.GratiM.KreyJ. F.WindsorA. M.SousaA. D.et al (2016). Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like. Nat. Commun.7, 10833. 10.1038/ncomms10833
54
EisenbergerT.Di DonatoN.BaigS. M.NeuhausC.BeyerA.DeckerE.et al (2014). Targeted and genomewide NGS data disqualify mutations in MYO1A, the "DFNA48 gene", as a cause of deafness. Hum. Mutat.35, 565–570. 10.1002/humu.22532
55
El-AmraouiA.SchonnJ. S.Kussel-AndermannP.BlanchardS.DesnosC.HenryJ. P.et al (2002). MyRIP, a novel Rab effector, enables myosin VIIa recruitment to retinal melanosomes. EMBO Rep.3, 463–470. 10.1093/embo-reports/kvf090
56
FangQ.IndzhykulianA. A.MustaphaM.RiordanG. P.DolanD. F.FriedmanT. B.et al (2015). The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing. Elife4, e08627. 10.7554/eLife.08627
57
FitzG. N.WeckM. L.BodnyaC.PerkinsO. L.TyskaM. J. (2023). Protrusion growth driven by myosin-generated force. Dev. Cell58, 18–33.e6. 10.1016/j.devcel.2022.12.001
58
FothB. J.GoedeckeM. C.SoldatiD. (2006). New insights into myosin evolution and classification. Proc. Natl. Acad. Sci. U. S. A.103, 3681–3686. 10.1073/pnas.0506307103
59
FriedmanT. B.BelyantsevaI. A.FrolenkovG. I. (2020). Myosins and hearing. Adv. Exp. Med. Biol.1239, 317–330. 10.1007/978-3-030-38062-5_13
60
FuX.ZhangL.JinY.SunX.ZhangA.WenZ.et al (2016). Loss of Myh14 increases susceptibility to noise-induced hearing loss in CBA/CaJ mice. Neural Plast.2016, 6720420. 10.1155/2016/6720420
61
Fujita-BeckerS.ReuboldT. F.HolmesK. C. (2006). The actin-binding cleft: functional characterisation of myosin II with a strut mutation. J. Muscle Res. Cell Motil.27, 115–123. 10.1007/s10974-005-9047-0
62
Galbis-MartinezL.Blanco-KellyF.Garcia-GarciaG.Avila-FernandezA.JaijoT.Fuster-GarciaC.et al (2021). Genotype-phenotype correlation in patients with Usher syndrome and pathogenic variants in MYO7A: implications for future clinical trials. Acta Ophthalmol.99, 922–930. 10.1111/aos.14795
63
GieseA. P. J.TangY. Q.SinhaG. P.BowlM. R.GoldringA. C.ParkerA.et al (2017). CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nat. Commun.8, 43. 10.1038/s41467-017-00061-1
64
GillespieP. G.MullerU. (2009). Mechanotransduction by hair cells: models, molecules, and mechanisms. Cell139, 33–44. 10.1016/j.cell.2009.09.010
65
GlowatzkiE.FuchsP. A. (2002). Transmitter release at the hair cell ribbon synapse. Nat. Neurosci.5, 147–154. 10.1038/nn796
66
GolombE.MaX.JanaS. S.PrestonY. A.KawamotoS.ShohamN. G.et al (2004). Identification and characterization of nonmuscle myosin II-C, a new member of the myosin II family. J. Biol. Chem.279, 2800–2808. 10.1074/jbc.M309981200
67
GoodyearR. J.LeganP. K.WrightM. B.MarcottiW.OganesianA.CoatsS. A.et al (2003). A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles. J. Neurosci.23, 9208–9219. 10.1523/JNEUROSCI.23-27-09208.2003
68
GratiM.KacharB. (2011). Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction. Proc. Natl. Acad. Sci. U. S. A.108, 11476–11481. 10.1073/pnas.1104161108
69
GratiM.ShinJ. B.WestonM. D.GreenJ.BhatM. A.GillespieP. G.et al (2012). Localization of PDZD7 to the stereocilia ankle-link associates this scaffolding protein with the Usher syndrome protein network. J. Neurosci.32, 14288–14293. 10.1523/JNEUROSCI.3071-12.2012
70
GratiM.YanD.RavalM. H.WalshT.MaQ.ChakchoukI.et al (2016). MYO3A causes human dominant deafness and interacts with protocadherin 15-CD2 isoform. Hum. Mutat.37, 481–487. 10.1002/humu.22961
71
GreenbergM. J.LinT.GoldmanY. E.ShumanH.OstapE. M. (2012). Myosin IC generates power over a range of loads via a new tension-sensing mechanism. Proc. Natl. Acad. Sci. U. S. A.109, E2433–E2440. 10.1073/pnas.1207811109
72
GrilletN.XiongW.ReynoldsA.KazmierczakP.SatoT.LilloC.et al (2009). Harmonin mutations cause mechanotransduction defects in cochlear hair cells. Neuron62, 375–387. 10.1016/j.neuron.2009.04.006
73
HeisslerS. M.MansteinD. J. (2011). Comparative kinetic and functional characterization of the motor domains of human nonmuscle myosin-2C isoforms. J. Biol. Chem.286, 21191–21202. 10.1074/jbc.M110.212290
74
HeisslerS. M.MansteinD. J. (2013). Nonmuscle myosin-2: mix and match. Cell Mol. Life Sci.70, 1–21. 10.1007/s00018-012-1002-9
75
HeisslerS. M.SellersJ. R. (2014). Myosin light chains: teaching old dogs new tricks. Bioarchitecture4, 169–188. 10.1080/19490992.2015.1054092
76
HokansonD. E.LaaksoJ. M.LinT.SeptD.OstapE. M. (2006). Myo1c binds phosphoinositides through a putative pleckstrin homology domain. Mol. Biol. Cell17, 4856–4865. 10.1091/mbc.e06-05-0449
77
HommaK.IkebeM. (2005). Myosin X is a high duty ratio motor. J. Biol. Chem.280, 29381–29391. 10.1074/jbc.M504779200
78
HommaK.SaitoJ.IkebeR.IkebeM. (2001). Motor function and regulation of myosin X. J. Biol. Chem.276, 34348–34354. 10.1074/jbc.M104785200
79
HoudusseA.SweeneyH. L. (2016). How myosin generates force on actin filaments. Trends Biochem. Sci.41, 989–997. 10.1016/j.tibs.2016.09.006
80
HoudusseA.TitusM. A. (2021). The many roles of myosins in filopodia, microvilli and stereocilia. Curr. Biol.31, R586–R602. 10.1016/j.cub.2021.04.005
81
JaiganeshA.De-La-TorreP.PatelA. A.TermineD. J.Velez-CortesF.ChenC.et al (2018). Zooming in on cadherin-23: structural diversity and potential mechanisms of inherited deafness. Structure26, 1210–1225. 10.1016/j.str.2018.06.003
82
JiangF.TakagiY.ShamsA.HeisslerS. M.FriedmanT. B.SellersJ. R.et al (2020). The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness. J. Biol. Chem.296, 100243. 10.1074/jbc.RA120.014903
83
JontesJ. D.MilliganR. A.PollardT. D.OstapE. M. (1997). Kinetic characterization of brush border myosin-I ATPase. Proc. Natl. Acad. Sci. U. S. A.94, 14332–14337. 10.1073/pnas.94.26.14332
84
KabahumaR. I.SchubertW. D.LabuschagneC.YanD.BlantonS. H.PepperM. S.et al (2021). Spectrum of MYO7A mutations in an indigenous South African population further elucidates the nonsyndromic autosomal recessive phenotype of DFNB2 to include both homozygous and compound heterozygous mutations. Genes (Basel)12, 274. 10.3390/genes12020274
85
KarolyiI. J.ProbstF. J.BeyerL.OdehH.DootzG.ChaK. B.et al (2003). Myo15 function is distinct from Myo6, Myo7a and pirouette genes in development of cochlear stereocilia. Hum. Mol. Genet.12, 2797–2805. 10.1093/hmg/ddg308
86
KatsunoT.BelyantsevaI. A.Cartagena-RiveraA. X.OhtaK.CrumpS. M.PetraliaR. S.et al (2019). TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing. JCI Insight4, e128561. 10.1172/jci.insight.128561
87
KawamotoS.AdelsteinR. S. (1991). Chicken nonmuscle myosin heavy chains: differential expression of two mRNAs and evidence for two different polypeptides. J. Cell Biol.112, 915–924. 10.1083/jcb.112.5.915
88
KazmierczakP.SakaguchiH.TokitaJ.Wilson-KubalekE. M.MilliganR. A.MullerU.et al (2007). Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature449, 87–91. 10.1038/nature06091
89
KerberM. L.JacobsD. T.CampagnolaL.DunnB. D.YinT.SousaA. D.et al (2009). A novel form of motility in filopodia revealed by imaging myosin-X at the single-molecule level. Curr. Biol.19, 967–973. 10.1016/j.cub.2009.03.067
90
KimS. V.MehalW. Z.DongX.HeinrichV.PypaertM.MellmanI.et al (2006). Modulation of cell adhesion and motility in the immune system by Myo1f. Science314, 136–139. 10.1126/science.1131920
91
KitajiriS.SakamotoT.BelyantsevaI. A.GoodyearR. J.StepanyanR.FujiwaraI.et al (2010). Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell141, 786–798. 10.1016/j.cell.2010.03.049
92
KomabaS.InoueA.MarutaS.HosoyaH.IkebeM. (2003). Determination of human myosin III as a motor protein having a protein kinase activity. J. Biol. Chem.278, 21352–21360. 10.1074/jbc.M300757200
93
KomabaS.WatanabeS.UmekiN.SatoO.IkebeM. (2010). Effect of phosphorylation in the motor domain of human myosin IIIA on its ATP hydrolysis cycle. Biochemistry49, 3695–3702. 10.1021/bi902211w
94
KovacsM.WangF.SellersJ. R. (2005). Mechanism of action of myosin X, a membrane-associated molecular motor. J. Biol. Chem.280, 15071–15083. 10.1074/jbc.M500616200
95
KreyJ. F.KrystofiakE. S.DumontR. A.VijayakumarS.ChoiD.RiveroF.et al (2016). Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid. J. Cell Biol.215, 467–482. 10.1083/jcb.201606036
96
KühneW. (1864). Untersuchungen über das Protoplasma und die Contractilität. Washington, D.C.: Biodiversity Heritage Library.
97
KurimaK.EbrahimS.PanB.SedlacekM.SenguptaP.MillisB. A.et al (2015). TMC1 and TMC2 localize at the site of mechanotransduction in mammalian inner ear hair cell stereocilia. Cell Rep.12, 1606–1617. 10.1016/j.celrep.2015.07.058
98
LalwaniA. K.GoldsteinJ. A.KelleyM. J.LuxfordW.CasteleinC. M.MhatreA. N. (2000). Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet.67, 1121–1128. 10.1016/S0002-9297(07)62942-5
99
LefevreG.MichelV.WeilD.LepelletierL.BizardE.WolfrumU.et al (2008). A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth. Development135, 1427–1437. 10.1242/dev.012922
100
LelliA.MichelV.Boutet De MonvelJ.CorteseM.Bosch-GrauM.AghaieA.et al (2016). Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth. J. Cell Biol.212, 231–244. 10.1083/jcb.201509017
101
Les EricksonF.CorsaA. C.DoseA. C.BurnsideB. (2003). Localization of a class III myosin to filopodia tips in transfected HeLa cells requires an actin-binding site in its tail domain. Mol. Biol. Cell14, 4173–4180. 10.1091/mbc.e02-10-0656
102
LewisJ. H.LinT.HokansonD. E.OstapE. M. (2006). Temperature dependence of nucleotide association and kinetic characterization of myo1b. Biochemistry45, 11589–11597. 10.1021/bi0611917
103
LiJ.ChenY.DengY.UnartaI. C.LuQ.HuangX.et al (2017). Ca(2+)-Induced rigidity change of the myosin VIIa IQ motif-single alpha helix lever arm extension. Structure25, 579–591 e574. 10.1016/j.str.2017.02.002
104
LiJ.LiuH.RavalM. H.WanJ.YengoC. M.LiuW.et al (2019). Structure of the MORN4/myo3a tail complex reveals MORN repeats as protein binding modules. Structure27, 1366–1374. 10.1016/j.str.2019.06.004
105
LiJ.ZhangM. (2020). Cargo binding by unconventional myosins. Adv. Exp. Med. Biol.1239, 21–40. 10.1007/978-3-030-38062-5_3
106
LiS.MeccaA.KimJ.CapraraG. A.WagnerE. L.DuT. T.et al (2020a). Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex. Nat. Commun.11, 2066. 10.1038/s41467-020-15936-z
107
LiY.LiuH.ZhaoX.HeD. Z. (2020b). Endolymphatic potential measured from developing and adult mouse inner ear. Front. Cell Neurosci.14, 584928. 10.3389/fncel.2020.584928
108
LinT.GreenbergM. J.MooreJ. R.OstapE. M. (2011). A hearing loss-associated myo1c mutation (R156W) decreases the myosin duty ratio and force sensitivity. Biochemistry50, 1831–1838. 10.1021/bi1016777
109
LiuH.LiJ.RavalM. H.YaoN.DengX.LuQ.et al (2016). Myosin III-mediated cross-linking and stimulation of actin bundling activity of Espin. Elife5, e12856. 10.7554/eLife.12856
110
LiuR.BillingtonN.YangY.BondC.HongA.SiththanandanV.et al (2021). A binding protein regulates myosin-7a dimerization and actin bundle assembly. Nat. Commun.12, 563. 10.1038/s41467-020-20864-z
111
LiuX. Z.WalshJ.MburuP.Kendrick-JonesJ.CopeM. J.SteelK. P.et al (1997). Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat. Genet.16, 188–190. 10.1038/ng0697-188
112
LoweyS.SaraswatL. D.LiuH.VolkmannN.HaneinD. (2007). Evidence for an interaction between the SH3 domain and the N-terminal extension of the essential light chain in class II myosins. J. Mol. Biol.371, 902–913. 10.1016/j.jmb.2007.05.080
113
ManorU.DisanzaA.GratiM.AndradeA.LinH.Di FioreP. P.et al (2011). Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Curr Biol.21 (2), 167–172. 10.1016/j.cub.2010.12.046
114
McphersonD. R. (2018). Sensory hair cells: an introduction to structure and Physiology. Integr. Comp. Biol.58, 282–300. 10.1093/icb/icy064
115
MehtaA. D.RockR. S.RiefM.SpudichJ. A.MoosekerM. S.CheneyR. E. (1999). Myosin-V is a processive actin-based motor. Nature400, 590–593. 10.1038/23072
116
MelchiondaS.AhituvN.BiscegliaL.SobeT.GlaserF.RabionetR.et al (2001). MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Am. J. Hum. Genet.69, 635–640. 10.1086/323156
117
MermallV.PostP. L.MoosekerM. S. (1998). Unconventional myosins in cell movement, membrane traffic, and signal transduction. Science279, 527–533. 10.1126/science.279.5350.527
118
MerrittR. C.ManorU.SallesF. T.GratiM.DoseA. C.UnrathW. C.et al (2012). Myosin IIIB uses an actin-binding motif in its espin-1 cargo to reach the tips of actin protrusions. Curr. Biol.22, 320–325. 10.1016/j.cub.2011.12.053
119
MhatreA. N.LiY.BhatiaN.WangK. H.AtkinG.LalwaniA. K. (2007). Generation and characterization of mice with Myh9 deficiency. Neuromolecular Med.9, 205–215. 10.1007/s12017-007-8008-8
120
MinozzoF.RassierD. E. (2013). “Myosin family classification,” in Encyclopedia of biophysics. Editor RobertsG. C. K. (Berlin, Heidelberg: Springer Berlin Heidelberg), 1658–1663.
121
MogensenM. M.RzadzinskaA.SteelK. P. (2007). The deaf mouse mutant whirler suggests a role for whirlin in actin filament dynamics and stereocilia development. Cell Motil. Cytoskelet.64, 496–508. 10.1002/cm.20199
122
MorelandZ. G.BirdJ. E. (2022). Myosin motors in sensory hair bundle assembly. Curr. Opin. Cell Biol.79, 102132. 10.1016/j.ceb.2022.102132
123
MorelandZ. G.JiangF.AguilarC.BarzikM.GongR.ShamsA.et al (2021). Myosin-driven nucleation of actin filaments drives stereocilia development critical for hearing. bioRxiv, 451618.
124
MorganC. P.KreyJ. F.GratiM.ZhaoB.FallenS.Kannan-SundhariA.et al (2016). PDZD7-MYO7A complex identified in enriched stereocilia membranes. Elife5, e18312. 10.7554/eLife.18312
125
MorrisC. A.WellsA. L.YangZ.ChenL. Q.BaldacchinoC. V.SweeneyH. L. (2003). Calcium functionally uncouples the heads of myosin VI. J. Biol. Chem.278, 23324–23330. 10.1074/jbc.M208957200
126
MukherjeaM.LlinasP.KimH.TravagliaM.SaferD.MenetreyJ.et al (2009). Myosin VI dimerization triggers an unfolding of a three-helix bundle in order to extend its reach. Mol. Cell35, 305–315. 10.1016/j.molcel.2009.07.010
127
NazS.GiguereC. M.KohrmanD. C.MitchemK. L.RiazuddinS.MorellR. J.et al (2002). Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am. J. Hum. Genet.71, 632–636. 10.1086/342193
128
NiuF.LiL.WangL.XiaoJ.XuS.LiuY.et al (2024). Autoinhibition and activation of myosin VI revealed by its cryo-EM structure. Nat. Commun.15, 1187. 10.1038/s41467-024-45424-7
129
O'connellC. B.TyskaM. J.MoosekerM. S. (2007). Myosin at work: motor adaptations for a variety of cellular functions. Biochim. Biophys. Acta1773, 615–630. 10.1016/j.bbamcr.2006.06.012
130
OstapE. M.PollardT. D. (1996). Biochemical kinetic characterization of the Acanthamoeba myosin-I ATPase. J. Cell Biol.132, 1053–1060. 10.1083/jcb.132.6.1053
131
PattonJ.BrewerC.ChienW.JohnstonJ. J.GriffithA. J.BieseckerL. G. (2016). A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness. Eur. J. Hum. Genet.25, 147–149. 10.1038/ejhg.2016.140
132
PeckhamM. (2011). Coiled coils and SAH domains in cytoskeletal molecular motors. Biochem. Soc. Trans.39, 1142–1148. 10.1042/BST0391142
133
PhichithD.TravagliaM.YangZ.LiuX.ZongA. B.SaferD.et al (2009). Cargo binding induces dimerization of myosin VI. Proc. Natl. Acad. Sci. U. S. A.106, 17320–17324. 10.1073/pnas.0909748106
134
PollardL. W.LordM. (2014). Getting myosin-V on the right track: tropomyosin sorts transport in yeast. Bioarchitecture4, 35–38. 10.4161/bioa.28204
135
PollardT. D.KornE. D. (1973). Acanthamoeba myosin. J. Biol. Chem.248, 4682–4690. 10.1016/s0021-9258(19)43718-6
136
PrellerM.MansteinD. J. (2013). Myosin structure, allostery, and mechano-chemistry. Structure21, 1911–1922. 10.1016/j.str.2013.09.015
137
PrellerM.MansteinD. J. (2017). “Myosin motors: structural aspects and functionality,” in Reference module in life sciences (Amsterdam, Netherlands: Elsevier).
138
PurvesD. (2018). Neuroscience. New York: Oxford University Press.
139
QuinteroO. A.MooreJ. E.UnrathW. C.ManorU.SallesF. T.GratiM.et al (2010). Intermolecular autophosphorylation regulates myosin IIIa activity and localization in parallel actin bundles. J. Biol. Chem.285, 35770–35782. 10.1074/jbc.M110.144360
140
QuinteroO. A.UnrathW. C.StevensS. M.Jr.ManorU.KacharB.YengoC. M. (2013). Myosin 3A kinase activity is regulated by phosphorylation of the kinase domain activation loop. J. Biol. Chem.288, 37126–37137. 10.1074/jbc.M113.511014
141
RanumP. T.GoodwinA. T.YoshimuraH.KolbeD. L.WallsW. D.KohJ. Y.et al (2019). Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing. Cell Rep.26, 3160–3171. 10.1016/j.celrep.2019.02.053
142
RavalM. H.QuinteroO. A.WeckM. L.UnrathW. C.GallagherJ. W.CuiR.et al (2016). Impact of the motor and tail domains of class III myosins on regulating the formation and elongation of actin protrusions. J. Biol. Chem.291, 22781–22792. 10.1074/jbc.M116.733741
143
RaymentI.RypniewskiW. R.Schmidt-BaseK.SmithR.TomchickD. R.BenningM. M.et al (1993). Three-dimensional structure of myosin subfragment-1: a molecular motor. Science261, 50–58. 10.1126/science.8316857
144
RaymentI.SmithC.YountR. G. (1996). The active site of myosin. Annu. Rev. Physiol.58, 671–702. 10.1146/annurev.ph.58.030196.003323
145
RehmanA. U.BirdJ. E.FaridiR.ShahzadM.ShahS.LeeK.et al (2016). Mutational spectrum of MYO15A and the molecular mechanisms of DFNB3 human deafness. Hum. Mutat.37, 991–1003. 10.1002/humu.23042
146
RiazuddinS.BelyantsevaI. A.GieseA. P.LeeK.IndzhykulianA. A.NandamuriS. P.et al (2012). Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat. Genet.44, 1265–1271. 10.1038/ng.2426
147
RiazuddinS.NazliS.AhmedZ. M.YangY.ZulfiqarF.ShaikhR. S.et al (2008). Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum. Mutat.29, 502–511. 10.1002/humu.20677
148
RzadzinskaA. K.NevalainenE. M.ProsserH. M.LappalainenP.SteelK. P. (2009). MyosinVIIa interacts with Twinfilin-2 at the tips of mechanosensory stereocilia in the inner ear. PLoS One4, e7097. 10.1371/journal.pone.0007097
149
SakaguchiH.TokitaJ.NaozM.Bowen-PopeD.GovN. S.KacharB. (2008). Dynamic compartmentalization of protein tyrosine phosphatase receptor Q at the proximal end of stereocilia: implication of myosin VI-based transport. Cell Motil. Cytoskelet.65, 528–538. 10.1002/cm.20275
150
SakaiT.UmekiN.IkebeR.IkebeM. (2011). Cargo binding activates myosin VIIA motor function in cells. Proc. Natl. Acad. Sci. U. S. A.108, 7028–7033. 10.1073/pnas.1009188108
151
SakamotoT.YildezA.SelvinP. R.SellersJ. R. (2005). Step-size is determined by neck length in myosin V. Biochemistry44, 16203–16210. 10.1021/bi0512086
152
SallesF. T.MerrittR. C.Jr.ManorU.DoughertyG. W.SousaA. D.MooreJ. E.et al (2009). Myosin IIIa boosts elongation of stereocilia by transporting espin 1 to the plus ends of actin filaments. Nat. Cell Biol.11, 443–450. 10.1038/ncb1851
153
SaposnikB.BinardS.FenneteauO.NurdenA.NurdenP.Hurtaud-RouxM. F.et al (2014). Mutation spectrum and genotype-phenotype correlations in a large French cohort of MYH9-Related Disorders. Mol. Genet. Genomic Med.2, 297–312. 10.1002/mgg3.68
154
SatoO.KomatsuS.SakaiT.TsukasakiY.TanakaR.MizutaniT.et al (2017). Human myosin VIIa is a very slow processive motor protein on various cellular actin structures. J. Biol. Chem.292, 10950–10960. 10.1074/jbc.M116.765966
155
SchefferD. I.ZhangD. S.ShenJ.IndzhykulianA.KaravitakiK. D.XuY. J.et al (2015). XIRP2, an actin-binding protein essential for inner ear hair-cell stereocilia. Cell Rep.10, 1811–1818. 10.1016/j.celrep.2015.02.042
156
SchultzJ. M.BhattiR.MadeoA. C.TurriffA.MuskettJ. A.ZalewskiC. K.et al (2011). Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes. J. Med. Genet.48, 767–775. 10.1136/jmedgenet-2011-100262
157
SchwanderM.KacharB.MullerU. (2010). Review series: the cell biology of hearing. J. Cell Biol.190, 9–20. 10.1083/jcb.201001138
158
SekerkovaG.RichterC. P.BartlesJ. R. (2011). Roles of the espin actin-bundling proteins in the morphogenesis and stabilization of hair cell stereocilia revealed in CBA/CaJ congenic jerker mice. PLoS Genet.7, e1002032. 10.1371/journal.pgen.1002032
159
SekiY.ShitaraH.IshiiR.OuchiT.YasudaS. P.KikkawaY. (2021). Myosin VI haploinsufficiency reduced hearing ability in mice. Neuroscience478, 100–111. 10.1016/j.neuroscience.2021.09.023
160
SelfT.MahonyM.FlemingJ.WalshJ.BrownS. D.SteelK. P. (1998). Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development125, 557–566. 10.1242/dev.125.4.557
161
SelfT.SobeT.CopelandN. G.JenkinsN. A.AvrahamK. B.SteelK. P. (1999). Role of myosin VI in the differentiation of cochlear hair cells. Dev. Biol.214, 331–341. 10.1006/dbio.1999.9424
162
SellersJ. R. (2000). Myosins: a diverse superfamily. Biochim. Biophys. Acta1496, 3–22. 10.1016/s0167-4889(00)00005-7
163
ShangG.BrautigamC. A.ChenR.LuD.Torres-VazquezJ.ZhangX. (2017). Structure analyses reveal a regulated oligomerization mechanism of the PlexinD1/GIPC/myosin VI complex. Elife6, e27322. 10.7554/eLife.27322
164
ShinC.FengY.ManleyJ. L. (2004). Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature427, 553–558. 10.1038/nature02288
165
ShinJ. B.Longo-GuessC. M.GagnonL. H.SaylorK. W.DumontR. A.SpinelliK. J.et al (2010). The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J. Neurosci.30, 9683–9694. 10.1523/JNEUROSCI.1541-10.2010
166
SimmD.HatjeK.KollmarM. (2017). Distribution and evolution of stable single α-helices (SAH domains) in myosin motor proteins. PLoS One12, e0174639. 10.1371/journal.pone.0174639
167
SolankiA. K.BiswalM. R.WalterhouseS.MartinR.KondkarA. A.KnolkerH. J.et al (2021). Loss of motor protein MYO1C causes rhodopsin mislocalization and results in impaired visual function. Cells10, 1322. 10.3390/cells10061322
168
SpinkB. J.SivaramakrishnanS.LipfertJ.DoniachS.SpudichJ. A. (2008). Long single alpha-helical tail domains bridge the gap between structure and function of myosin VI. Nat. Struct. Mol. Biol.15, 591–597. 10.1038/nsmb.1429
169
SpudichG.ChibalinaM. V.AuJ. S.ArdenS. D.BussF.Kendrick-JonesJ. (2007). Myosin VI targeting to clathrin-coated structures and dimerization is mediated by binding to Disabled-2 and PtdIns(4,5)P2. Nat. Cell Biol.9, 176–183. 10.1038/ncb1531
170
StaufferE. A.ScarboroughJ. D.HironoM.MillerE. D.ShahK.MercerJ. A.et al (2005). Fast adaptation in vestibular hair cells requires myosin-1c activity. Neuron47, 541–553. 10.1016/j.neuron.2005.07.024
171
SweeneyH. L.HolzbaurE. L. F. (2018). Motor proteins. Cold Spring Harb. Perspect. Biol.10, a021931. 10.1101/cshperspect.a021931
172
SweeneyH. L.HoudusseA. (2010). Structural and functional insights into the Myosin motor mechanism. Annu. Rev. Biophys.39, 539–557. 10.1146/annurev.biophys.050708.133751
173
TadenevA. L. D.AkturkA.DevanneyN.MathurP. D.ClarkA. M.YangJ.et al (2019). GPSM2-GNAI specifies the tallest stereocilia and defines hair bundle row identity. Curr. Biol.29, 921–934. 10.1016/j.cub.2019.01.051
174
TaftM. H.LathamS. L. (2020). “Myosin XVIII,” in Myosins: a superfamily of molecular motors. Editor ColuccioL. M. (Cham: Springer International Publishing), 421–438.
175
TakagiY.FarrowR. E.BillingtonN.NagyA.BattersC.YangY.et al (2014). Myosin-10 produces its power-stroke in two phases and moves processively along a single actin filament under low load. Proc. Natl. Acad. Sci. U. S. A.111, E1833–E1842. 10.1073/pnas.1320122111
176
TamagawaY.IshikawaK.IshikawaK.IshidaT.KitamuraK.MakinoS.et al (2002). Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation. Laryngoscope112, 292–297. 10.1097/00005537-200202000-00017
177
ThirumuruganK.SakamotoT.HammerJ. A.3rdSellersJ. R.KnightP. J. (2006). The cargo-binding domain regulates structure and activity of myosin 5. Nature442, 212–215. 10.1038/nature04865
178
TrouilletA.MillerK. K.GeorgeS. S.WangP.AliN. E.RicciA.et al (2021). Loxhd1 mutations cause mechanotransduction defects in cochlear hair cells. J. Neurosci.41, 3331–3343. 10.1523/JNEUROSCI.0975-20.2021
179
TyskaM. J.MackeyA. T.HuangJ. D.CopelandN. G.JenkinsN. A.MoosekerM. S. (2005). Myosin-1a is critical for normal brush border structure and composition. Mol. Biol. Cell16, 2443–2457. 10.1091/mbc.e04-12-1116
180
UdovichenkoI. P.GibbsD.WilliamsD. S. (2002). Actin-based motor properties of native myosin VIIa. J. Cell Sci.115, 445–450. 10.1242/jcs.115.2.445
181
UmekiN.JungH. S.WatanabeS.SakaiT.LiX. D.IkebeR.et al (2009). The tail binds to the head-neck domain, inhibiting ATPase activity of myosin VIIA. Proc. Natl. Acad. Sci. U. S. A.106, 8483–8488. 10.1073/pnas.0812930106
182
VerpyE.LeiboviciM.ZwaenepoelI.LiuX. Z.GalA.SalemN.et al (2000). A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat. Genet.26, 51–55. 10.1038/79171
183
Vicente-ManzanaresM.MaX.AdelsteinR. S.HorwitzA. R. (2009). Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat. Rev. Mol. Cell Biol.10, 778–790. 10.1038/nrm2786
184
WalavalkarK.NotaniD. (2020). Beyond the coding genome: non-coding mutations and cancer. Front. Biosci. (Landmark Ed.)25, 1828–1838. 10.2741/4879
185
WalshT.WalshV.VreugdeS.HertzanoR.ShahinH.HaikaS.et al (2002). From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc. Natl. Acad. Sci. U. S. A.99, 7518–7523. 10.1073/pnas.102091699
186
WangA.LiangY.FridellR. A.ProbstF. J.WilcoxE. R.TouchmanJ. W.et al (1998). Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science280, 1447–1451. 10.1126/science.280.5368.1447
187
WangF.HarveyE. V.ContiM. A.WeiD.SellersJ. R. (2000). A conserved negatively charged amino acid modulates function in human nonmuscle myosin IIA. Biochemistry39, 5555–5560. 10.1021/bi000133x
188
WangemannP. (2006). Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. J. Physiol.576, 11–21. 10.1113/jphysiol.2006.112888
189
WatanabeS.IkebeR.IkebeM. (2006). Drosophila myosin VIIA is a high duty ratio motor with a unique kinetic mechanism. J. Biol. Chem.281, 7151–7160. 10.1074/jbc.M511592200
190
WeilD.BlanchardS.KaplanJ.GuilfordP.GibsonF.WalshJ.et al (1995). Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature374, 60–61. 10.1038/374060a0
191
WeilD.El-AmraouiA.MasmoudiS.MustaphaM.KikkawaY.LaineS.et al (2003). Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum. Mol. Genet.12, 463–471. 10.1093/hmg/ddg051
192
WeilD.KusselP.BlanchardS.LevyG.Levi-AcobasF.DriraM.et al (1997). The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat. Genet.16, 191–193. 10.1038/ng0697-191
193
WellsA. L.LinA. W.ChenL. Q.SaferD.CainS. M.HassonT.et al (1999). Myosin VI is an actin-based motor that moves backwards. Nature401, 505–508. 10.1038/46835
194
YamamotoN.OkanoT.MaX.AdelsteinR.S.KelleyM.W. (2009). Myosin II regulates extension, growth and patterning in the mammalian cochlear duct. Development136, 1977–1986. 10.1242/dev.030718
195
YengoC. M.TakagiY.SellersJ. R. (2012). Temperature dependent measurements reveal similarities between muscle and non-muscle myosin motility. J. Muscle Res. Cell Motil.33, 385–394. 10.1007/s10974-012-9316-7
196
YountR. G.LawsonD.RaymentI. (1995). Is myosin a "back door" enzyme?Biophys. J.68, 44S–49S.
197
YuC.FengW.WeiZ.MiyanoiriY.WenW.ZhaoY.et al (2009). Myosin VI undergoes cargo-mediated dimerization. Cell138, 537–548. 10.1016/j.cell.2009.05.030
198
ZadroC.AlemannoM. S.BellacchioE.FicarellaR.DonaudyF.MelchiondaS.et al (2009). Are MYO1C and MYO1F associated with hearing loss?Biochim. Biophys. Acta1792, 27–32. 10.1016/j.bbadis.2008.10.017
199
ZampiniV.RuttigerL.JohnsonS. L.FranzC.FurnessD. N.WaldhausJ.et al (2011). Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS Biol.9, e1001048. 10.1371/journal.pbio.1001048
200
ZhangF.LupskiJ. R. (2015). Non-coding genetic variants in human disease. Hum. Mol. Genet.24, R102–R110. 10.1093/hmg/ddv259
201
ZhangY.ContiM. A.MalideD.DongF.WangA.ShmistY. A.et al (2012). Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A. Blood119, 238–250. 10.1182/blood-2011-06-358853
202
ZhaoB.WuZ.GrilletN.YanL.XiongW.Harkins-PerryS.et al (2014). TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron84, 954–967. 10.1016/j.neuron.2014.10.041
203
ZhaoH.PykäläinenA.LappalainenP. (2011). I-BAR domain proteins: linking actin and plasma membrane dynamics. Curr. Opin. Cell Biol.23, 14–21. 10.1016/j.ceb.2010.10.005
204
ZhengL.SekerkováG.VranichK.TilneyL. G.MugnainiE.BartlesJ. R. (2000). The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins. Cell102, 377–385. 10.1016/s0092-8674(00)00042-8
205
ZinaZ. B.MasmoudiS.AyadiH.ChakerF.GhorbelA. M.DriraM.et al (2001). From DFNB2 to Usher syndrome: variable expressivity of the same disease. Am. J. Med. Genet.101, 181–183. 10.1002/ajmg.1335
Summary
Keywords
hearing, myosin, stereocilia, cargo transport, hereditary deafness
Citation
Miyoshi T, Belyantseva IA, Sajeevadathan M and Friedman TB (2024) Pathophysiology of human hearing loss associated with variants in myosins. Front. Physiol. 15:1374901. doi: 10.3389/fphys.2024.1374901
Received
24 January 2024
Accepted
21 February 2024
Published
18 March 2024
Volume
15 - 2024
Edited by
Manuel H. Taft, Hannover Medical School, Germany
Reviewed by
Kazuaki Homma, Northwestern University, United States
Richard Cheney, University of North Carolina at Chapel Hill, United States
Updates
Copyright
© 2024 Miyoshi, Belyantseva, Sajeevadathan and Friedman.
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*Correspondence: Takushi Miyoshi, tmiyoshi26@siumed.edu
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