HGNC Approved Gene Symbol: MYO6
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38): 6:75,749,239-75,919,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.1 | Deafness, autosomal dominant 22 | 606346 | Autosomal dominant | 3 |
| Deafness, autosomal dominant 22, with hypertrophic cardiomyopathy | 606346 | Autosomal dominant | 3 | |
| Deafness, autosomal recessive 37 | 607821 | Autosomal recessive | 3 |
Myosin VI, one of the so-called unconventional myosins, is an actin-based molecular motor involved in intracellular vesicle and organelle transport (Rock et al., 2001; Hasson and Mooseker, 1994). Myosin VI participates in 2 steps of endocytic trafficking; it is recruited to both clathrin (see CLTC; 118955)-coated pits and to ensuing uncoated endocytic vesicles (Naccache et al., 2006).
Hasson and Mooseker (1994) characterized porcine myosin VI. Avraham et al. (1995) showed that the sequence of the mouse Myo6 gene is 87% identical to that of the pig. The mouse cDNA predicted a protein of 1,266 amino acids with a relative molecular mass of 142 kD. In the pig, rat, and mouse, myosin VI is widely expressed. In the mouse, within the cochlea of the inner ear, myosin VI is expressed specifically within the sensory hair cells. Avraham et al. (1995) found that the Myo6 gene is defective in the Snell's waltzer (sv) mouse mutant, which is associated with deafness. Together with the expression pattern in the sensory hair cells of the cochlea, this suggested to the authors that myosin VI is required for normal hearing and that the human homolog is a candidate for a human recessive deafness gene.
Avraham et al. (1997) cloned and characterized the human MYO6 cDNA. Expression of MYO6 in human fetal cochlea demonstrated the importance of myosin VI in the mammalian inner ear and supported its potential role in human inner ear pathology.
Vreugde et al. (2006) identified 5 putative monopartite nuclear localization signals and 1 putative bipartite nuclear localization signal in MYO6, mainly in the tail region. In the first part of the tail region, they identified a putative protein-protein interaction domain consisting of glutamic acid- and arginine-rich regions. Immunofluorescence and cellular fractionation of human and other mammalian cells revealed a proportion of MYO6 in the nucleus, where it colocalized with RNA polymerase II (see 180660) and nascent transcripts. MYO6 in the nuclear fraction had an apparent molecular mass of 150 kD.
Ahituv et al. (2000) determined that the MYO6 gene contains 32 exons and spans 70 kb. They found that exon 30, which contains a putative casein kinase II (see 115440) site, is alternatively spliced and appears only in fetal and adult brain.
Avraham et al. (1995) suggested that the human MYO6 gene may map to the centromeric region of chromosome 6, a region that shows syntenic homology with the portion of mouse chromosome 9 where the Snell's waltzer (sv) mouse mutation is located. On the basis of location of the Myo6 gene in the mouse, Hasson et al. (1996) predicted that the homologous human gene is located on 6p12-q16.3. By fluorescence in situ hybridization, Avraham et al. (1997) mapped the MYO6 gene to 6q13. In the mouse, Myo6 maps between Gsta and Htr1b; the human homologs, GSTA2 (138360) and HTR1B (182131), both map to chromosome 6.
Rock et al. (2001) noted that myosin VI moves toward the pointed end of actin (see 102560), whereas all other characterized myosins move toward the barbed end. They found that porcine myosin VI took much larger steps than expected. Unlike other characterized myosins, myosin VI stepping was highly irregular, with a broad distribution of step sizes.
Rock et al. (2005) showed that the proximal tail region of porcine myosin VI is a flexible domain that permits the myosin heads to separate and allows the large and variable step size of myosin VI.
MYO6 is thought to function as both a transporter and an anchor. Altman et al. (2004) noted that in vitro studies had suggested possible mechanisms for processive stepping, but a biochemical basis for anchoring had not been demonstrated. Using optical trapping, they observed MYO6 stepping against applied forces. Step size was not strongly affected by such loads. At saturating ATP, MYO6 kinetics showed little dependence on load until, at forces near stall, its stepping slowed dramatically as load increased. At subsaturating ATP or in the presence of ADP, stepping kinetics were significantly inhibited by load.
Naccache et al. (2006) found that Myo6 recruitment to uncoated endocytic vesicles in cultured mouse kidney epithelial cells was dependent on synectin (GIPC1; 605072). Myo6 bound a C-terminal domain of synectin, and Myo6 recruitment required the interaction between the PDZ-binding domains of engulfed receptors, such as megalin (LRP2; 600073), and the PDZ domain of synectin.
Vreugde et al. (2006) found that colocalization and interaction of MYO6 with RNA polymerase II required transcriptional activity. Pharmacologic blockade of transcription resulted in redistribution of nuclear MYO6 to the cytoplasm. Chromatin immunoprecipitation assays showed that MYO6 was recruited to the promoters and intragenic regions of active genes, but not to noncoding, nonregulatory intergenic regions. Downregulation of MYO6 reduced steady-state mRNA levels of the regulated genes in vivo, and antibodies to MYO6 reduced transcription in vitro. Vreugde et al. (2006) concluded that MYO6 modulates RNA polymerase II-dependent transcription of active genes and suggested that an actin-myosin-based mechanism may be involved in transcription.
Otoferlin (OTOF; 603681) has been proposed to be the calcium sensor in hair cell exocytosis, compensating for the classic synaptic fusion proteins synaptotagmin-1 (SYT1; 185605) and synaptotagmin-2 (SYT2; 600104). Heidrych et al. (2009) demonstrated in a yeast 2-hybrid assay that myosin VI is a novel otoferlin-binding partner. Coimmunoprecipitation assay and coexpression suggested an interaction of both proteins within the basolateral part of inner hair cells (IHCs). Comparison of Otof- and Myo6-mutant mice indicated noncomplementary and complementary roles of myosin VI and otoferlin for synaptic maturation. IHCs from Otof-mutant mice exhibited a decoupling of Ctbp2 (602619) and CaV1.3 (CACNA1D; 114206) and severe reduction of exocytosis. Myo6-mutant IHCs failed to transport BK channels to the membrane of the apical cell regions, and the exocytotic Ca(2+) efficiency did not mature. Otof- and Myo6-mutant IHCs showed a reduced basolateral synaptic surface area and altered active zone topography. Membrane infoldings in Otof-mutant IHCs indicated disturbed transport of endocytotic membranes and linked the above morphologic changes to a complementary role of otoferlin and myosin VI in transport of intracellular compartments to the basolateral inner hair cell membrane.
Cryoelectron Microscopy
Wells et al. (1999) visualized the myosin VI construct bound to actin (see 102560) using cryoelectron microscopy and image analysis, and found that an ADP-mediated conformational change in the domain distal to the motor, a structure likely to be the effective lever arm, is in the opposite direction to that observed for other myosins. Wells et al. (1999) concluded that myosin VI achieves reverse-direction movement by rotating its lever arm in the opposite direction to conventional myosin lever arm movement.
Crystal Structure
Menetrey et al. (2005) solved the crystal structure of a truncated version of the reverse-direction myosin motor, myosin VI, containing the motor domain and binding sites of 2 calmodulin (114180) molecules at a resolution of 2.4 angstroms. The structure revealed only minor differences in the motor domain from that in plus end-directed myosins, with the exception of 2 unique inserts. The first is near the nucleotide-binding pocket and alters the rates of nucleotide association and dissociation. The second unique insert forms an integral part of the myosin VI converter domain along with a calmodulin bound to a novel target motif within the insert. This serves to redirect the effective lever arm of myosin VI, which includes a second calmodulin bound to an IQ motif, towards the pointed (minus) end of the actin filament. This repositioning largely accounts for the reverse directionality of this class of myosin motors. Menetrey et al. (2005) proposed a model incorporating a kinesin-like uncoupling/docking mechanism to provide a full explanation of the movements of myosin VI.
Electron Microscopy
Roux et al. (2009) showed that Myo6 was present at the synaptic active zone of IHCs by immunogold electron microscopy. In Myo6(sv/sv) mice, ionic currents and ribbon synapse maturation of IHCs proceeded normally until at least postnatal day 6. In adult Myo6(sv/sv) mice, however, the IHCs displayed immature potassium currents and still fired action potentials, as normally only observed in immature IHCs. In addition, the number of ribbons per IHC was reduced, and some of the remaining ribbons were morphologically immature. Calcium-dependent exocytosis was markedly reduced despite normal calcium currents and a large proportion of morphologically mature synapses. Yeast 2-hybrid assay, in vitro binding assays, and immunoprecipitation studies of transfected HEK-293 cells and mouse cochlear sensory epithelium showed direct interaction of Myo6 and otoferlin (OTOF; 603681). Immunogold electron microscopy showed that Myo6 and otoferlin colocalized at the edge of the synaptic active zone in mouse IHCs. Roux et al. (2009) suggested that MYO6/otoferlin interaction may be involved in the recycling of synaptic vesicles.
Deafness, Autosomal Dominant 22
In a large family segregating autosomal dominant nonsyndromic sensorineural hearing loss, Melchionda et al. (2001) demonstrated linkage of the disorder to 6q13 (DFNA22; 606346) and identified a missense mutation in the MYO6 gene (C442Y; 600970.0001) in all affected members.
In affected members of a kindred in which autosomal dominant sensorineural deafness cosegregated with familial hypertrophic cardiomyopathy, Mohiddin et al. (2004) identified a his246-to-arg mutation in the MYO6 gene (H246R; 600970.0005).
In a large Danish family with 18 affected members segregating autosomal dominant nonsyndromic hearing loss (DFNA22; 606346), Sanggaard et al. (2008) detected heterozygosity for a nonsense mutation in the MYO6 gene (R849X; 600970.0006).
Hilgert et al. (2008) analyzed the MYO6 gene in 2 Belgian families with autosomal dominant deafness mapping to the DFNA22 locus and identified a splice site mutation (600970.0007) in 'family 2.' No mutation was identified in 'family 1,' although quantitative real-time PCR revealed 1.5- to 1.8-fold overexpression of MYO6 in patients compared to controls. After exclusion of gene duplication, the authors suggested that most likely the overexpression in 'family 1' involved a mutation in an as yet unidentified regulatory region of the MYO6 gene.
Deafness, Autosomal Recessive 37
Ahmed et al. (2003) identified mutations in the MYO6 gene in 3 families segregating autosomal recessive congenital sensorineural deafness (DFNB37; 607821); see 600970.0002-600970.0004.
Deafness, Sensorineural, with Hypertrophic Cardiomyopathy
In affected members of a kindred in which autosomal dominant sensorineural deafness cosegregated with familial hypertrophic cardiomyopathy (see 606346), Mohiddin et al. (2004) identified a heterozygous missense mutation in the MYO6 gene (H246R; 600970.0005).
Geisbrecht and Montell (2002) found that depletion of Myo6 from a small group of migratory follicle cells of Drosophila, known as border cells, inhibited their migration. Cells lacking Myo6 also lacked E-cadherin (192090) and beta-catenin (116806). Conversely, cells lacking E-cadherin or beta-catenin showed reduced levels of Myo6. Geisbrecht and Montell (2002) concluded that, in Drosophila, Myo6 is required for border cell migration where it stabilizes E-cadherin and beta-catenin.
The MYO15 (602666), MYO6, and MYO7A (276903) genes are essential for hearing in both humans and mice. Despite widespread expression, homozygosity for mutations in these genes only results in auditory or ocular dysfunction. The pirouette (pi) mouse exhibits deafness and inner ear pathology resembling that of Myo15 mutant mice. Karolyi et al. (2003) crossed Myo15 mutant mice to Myo6, Myo7a, and pi mutant mouse strains. Viable double-mutant homozygotes were obtained from each cross, and hearing in doubly heterozygous mice was similar to singly heterozygous mice. All critical cell types of the cochlear sensory epithelium were present in double-mutant mice, and cochlear stereocilia exhibited a superimposition of single-mutant phenotypes. Karolyi et al. (2003) suggested that the function of Myo15 is distinct from that of Myo6, Myo7a, or pi in development and/or maintenance of stereocilia.
Melchionda et al. (2001) studied a large Italian kindred affected by progressive, postlingual sensorineural deafness linked to chromosome 6q13 (606346). Mutation analysis of the MYO6 gene demonstrated that all affected members of the family had a G-to-A transition in exon 12 at position 1325 of the cDNA sequence (relative to the ATG, designated +1), which replaces a cysteine (TGT) with a tyrosine (TAT) at residue 442 of the protein (C442Y).
By in vitro expression studies, Sato et al. (2004) found that the C442Y mutation caused several major changes in myosin VI mechanoenzymatic function. The C442Y mutant protein had an approximately 10-fold increase in the rate of ADP dissociation from myosin VI, and there was an approximately 10-fold increase in the ATPase rate in the absence of actin compared to wildtype. There was a 2-fold increase in the actin gliding velocity of the mutant protein compared to wildtype. The findings suggested that the mutation impedes the processive movement of myosin VI.
In a Pakistani family segregating autosomal recessive congenital profound sensorineural deafness (DFNB37; 607821), Ahmed et al. (2003) identified homozygosity for a 1-bp insertion (36insT) in exon 2 of the MYO6 gene in all 6 affected individuals. The insertion was predicted to cause a frameshift and premature translation termination after the first 12 amino acids of myosin VI. The oldest affected child also had congenital stationary night blindness and retinal pigment epithelial changes; the other 5 affected children with profound deafness were less than 30 months of age.
In a Pakistani family segregating autosomal recessive congenital profound sensorineural deafness (DFNB37; 607821), Ahmed et al. (2003) identified homozygosity for a 3496C-T transition in exon 32 of the MYO6 gene, resulting in an arg1166-to-ter (R1166X) substitution, in all affected members.
In a Pakistani family segregating autosomal recessive congenital profound sensorineural deafness (DFNB37; 607821), Ahmed et al. (2003) identified homozygosity for a 647A-T transversion in the MYO6 gene, resulting in a glu216-to-val (E216V) substitution, in the single affected member.
In affected members of a kindred in which autosomal dominant sensorineural deafness cosegregated with familial hypertrophic cardiomyopathy (see 606346), Mohiddin et al. (2004) identified a 737A-G transition in the MYO6 gene, resulting in a his246-to-arg (H246R) mutation within the highly conserved motor domain of the protein. The sensorineural hearing loss, which was progressive and late in onset, was present in 10 members, 4 of whom also had hypertrophic cardiomyopathy. Six had sensorineural hearing loss without echocardiographic evidence of left ventricular hypertrophy; 4 of these 6 patients, however, had abnormalities on 12-lead ECG, and 3 of the 6 had prolongation of the QT interval. Cardiac symptoms were mild or absent in most affected family members. Mohiddin et al. (2004) suggested that the cardiac manifestations may have escaped detection in affected members of previously reported pedigrees with MYO6-associated sensorineural hearing loss.
In a large Danish family with postlingual sensorineural hearing loss mapping to chromosome 6p12.1-q16.1 (606346), Sanggaard et al. (2008) identified a heterozygous 2545C-T transition in exon 25 of the MYO6 gene, resulting in an arg849-to-ter (R849X) mutation.
In 11 affected members of a 5-generation Belgian family ('family 2') segregating autosomal dominant deafness (DFNA22; 606346), Hilgert et al. (2008) identified heterozygosity for a 2321T-G transversion in intron 23 of the MYO6 gene, creating a new splice donor site and resulting in the insertion of a 108-bp intronic fragment that causes a frameshift and a premature termination codon 16 nucleotides downstream of exon 23. The mutation was not found in unaffected family members or in 139 unrelated ethnically matched controls. Expression assays showed that patients had 80-85% of the MYO6 expression level of unaffected individuals, but the difference was not statistically significant.
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