Alternative titles; symbols
HGNC Approved Gene Symbol: MYO7A
Cytogenetic location: 11q13.5 Genomic coordinates (GRCh38): 11:77,128,246-77,215,241 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.5 | Deafness, autosomal dominant 11 | 601317 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 2 | 600060 | Autosomal recessive | 3 | |
| Usher syndrome, type 1B | 276900 | Autosomal recessive | 3 |
The MYO7A gene encodes a protein classified as an unconventional myosin. Unconventional myosins are motor molecules with structurally conserved heads that move along actin filaments. Their highly divergent tails are presumed to be tethered to different macromolecular structures that move relative to actin filaments, thus enabling them to transport cargo (Weil et al., 1995).
By positional cloning, Weil et al. (1995) identified the MYO7A gene within the candidate gene region for Usher syndrome type IB (USH1B; see 276900) on chromosome 11q. Clones corresponding to the gene were isolated from a retinal cDNA library. The deduced protein encoded most of the motor head of myosin and was 95% identical to the mouse protein. RT-PCR products were detected in human kidney, liver, and retina, but not in brain or lymphocytes transformed by Epstein-Barr virus.
Weil et al. (1996) presented the cDNA sequence of myosin VIIA which predicted a 2,215-amino acid protein with a typical unconventional myosin structure. The protein was expected to dimerize into a 2-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily (see 130500). Several alternatively spliced isoforms were identified. In situ hybridization analysis in human embryos demonstrated MYO7A expression in the retinal pigment epithelium and photoreceptor cells, as well as in cochlear and vestibular neuroepithelia.
Gibson et al. (1995) identified the mouse Myo7a gene as being causative for the shaker-1 (sh1) phenotype, which is characterized by cochlear and vestibular dysfunction, but no retinal abnormalities. The authors identified the gene using positional cloning based on the fact that the olfactory marker protein gene (Omp) is very tightly linked to the mouse sh1 mutation on mouse chromosome 7. Among the 9 unique exon-trap products found in a YAC from this region, there was 1 that was used to isolate a 4.6-kb clone from a mouse inner-ear cDNA library. Sequence analysis demonstrated that this was the gene encoding myosin VIIA. The findings of both Weil et al. (1995) and Gibson et al. (1995) indicated that USH1B and 'shaker' are primary cytoskeletal protein defects.
Chen et al. (1996) cloned cDNAs encoding a previously unexplored portion of the MYO7A gene. Two transcripts were found, one encoding the predicted 250-kD protein and another encoding a shorter form. Both transcripts were found in highest abundance in testis, although the shorter one was much less abundant. Both were detected in lymphocytes by RT-PCR. The myosin tail encoded by the long transcript includes a long repeat of approximately 460 amino acids. Each repeat contains a novel 'MyTH4' domain similar to domains in 3 other myosins, and a domain similar to the membrane-associated portion of talin (186745) and other members of the band 4.1 family.
Kelley et al. (1997) found that the largest mRNA transcript is 7.4 kb.
Weil et al. (1996) determined that the MYO7A gene contains 48 coding exons.
Kelley et al. (1997) reported that the MYO7A gene spans 120 kb and has 49 exons.
By in situ hybridization analysis in human embryos, Weil et al. (1996) demonstrated that the MYO7A was expressed in the pigment epithelium and the photoreceptor cells of the retina, indicating to the authors that both cell types may be involved in the retinal degenerative process in Usher syndrome type IB. The gene was also expressed in the human embryonic cochlear and vestibular neuroepithelia. Weil et al. (1996) suggested that deafness and vestibular dysfunction in Usher syndrome patients results from a defect in the morphogenesis of the inner ear sensory cell stereocilia.
El-Amraoui et al. (1996) found that MYO7A was expressed in human embryo retinal pigment epithelium at 6, 9 and 10 weeks. From 18 to 19 weeks on and in the adult, MYO7A was present in both the pigment epithelium and the photoreceptor cells. MYO7A was mainly present in the inner segments, the base of the outer segments, and the synaptic endings of photoreceptor cells. Myo7a was not expressed in mouse photoreceptor cells, but was expressed in pigment epithelium cells. MYO7A was also expressed in cochlear hair cells during mouse embryonic development and in sensory hair cells in developing human otic vesicle, which correlated with the vestibular and cochlear dysfunctions resulting in balance problems and hearing impairment observed in both Usher patients and shaker-1 mouse mutants. The findings also indicated that the retinal abnormalities in USH1B result from a primary rod and cone defect, and that the shaker-1 mouse phenotype has no retinal defect since Myo7a is absent from the photoreceptor cells in rodents.
Boeda et al. (2002) noted that 3 distinct genetic forms of Usher syndrome, USH1B, USH1D (601607), and USH1C (276904), are caused by defects in the MYO7A, CDH23 (605516), and harmonin (USH1C; 605242) genes, respectively. They observed severely disorganized hair bundles in shaker-1 mice, and immunohistochemical analysis of differentiating hair cells indicated that Cdh23 was distributed normally in these mice, but harmonin b was not. Using human and mouse cDNA constructs and cells, they provided evidence that harmonin b anchors CDH23 to the stereocilia microfilaments and interacts directly with MYO7A, which conveys harmonin b along the actin core of the developing stereocilia. Boeda et al. (2002) proposed that the shaping of the hair bundle relies on a functional unit composed of MYO7A, harmonin b, and CDH23 and that the interaction of these proteins ensures the cohesion of the stereocilia.
Bahloul et al. (2010) found that both isoforms of mouse Cdh23 bound directly to the harmonin A isoform and to the tail of myosin-7a. The 3 proteins formed a complex that interacted with phosphatidylinositol 4,5-bisphosphate in synthetic liposomes. Knockout of Cdh23 in mice resulted in loss of harmonin from the apex of hair bundles in the organ of Corti and caused redistribution of a weakened myosin-7a signal along stereocilia.
Crystal Structure
Wu et al. (2011) reported the crystal structure of the MyTH4-FERM domains of MYO7A in complex with the central domain (CEN) of SANS (607696) at 2.8-angstrom resolution. The MyTH4 and FERM domains form an integral structural and functional supramodule binding to 2 highly conserved segments (CEN1 and 2) of SANS. Wu et al. (2011) concluded that the MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM.
Usher Syndrome Type IB
Weil et al. (1995) noted that the phenotype of Usher syndrome reflects cytoskeletal abnormalities, including abnormal organization of microtubules in the axoneme of photoreceptor cells (connecting cilium), nasal cilia cells, and sperm cells, as well as widespread degeneration of the organ of Corti. In affected members of 5 unrelated families with Usher syndrome IB, Weil et al. (1995) identified 5 different mutations in the MYO7A gene (276903.0001-276903.0005).
Among 189 patients with Usher syndrome type I, Weston et al. (1996) identified 13 different mutations within the N-terminal coding portion of the motor domain of MYO7A. The mutations segregated with the disease in 20 families. Two mutations, R212H (276903.0004) and R212C (276903.0005), accounted for the greatest percentage of observed mutant alleles (31% or 8/23 alleles). Three patients were homozygotes or compound heterozygotes for mutant alleles. All the other USH1B mutations observed were present in heterozygous state, and it was presumed that the mutation on the other allele was present in an unscreened region of the gene. None of the mutations reported by Weston et al. (1996) were observed in 96 unrelated control samples.
Levy et al. (1997) designed primers covering the complete MYO7A coding sequence, as well as the 3-prime noncoding sequence, allowing direct sequence analysis of 48 coding exons and flanking splice sites in 7 patients with USH1B. They identified 4 novel mutations.
Adato et al. (1997) screened USH1B families from 12 different ethnic groups for the presence of mutations in all 49 exons of the MYO7A gene. In 15 families, MYO7A mutations were detected, verifying their classification as USH1B. All of these mutations were novel, including 3 missense mutations, 1 premature stop codon, 2 splicing mutations, 1 frameshift, and 1 deletion of more than 2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than 1 family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. None of the 20 known USH1B mutations reported previously in other populations of the world were identified in these families, which although studied in Tel Aviv, were derived from many areas of the world.
Ouyang et al. (2005) carried out a systematic mutation screening of the genes known to cause type I Usher syndrome in patients from the U.S. and U.K. They identified a total of 27 different mutations. Approximately 35 to 39% of the observed mutations involved the USH1B (MYO7A) and USH1D (CDH23; 605516) genes. Two of the 12 MYO7A mutations they found, R666X (276903.0016) and IVS27-1G-C (276903.0017), accounted for 38% of the mutations found at that locus.
Riazuddin et al. (2008) identified 17 homozygous mutant alleles in the MYO7A gene, including 14 novel mutations, in affected members of 23 consanguineous Pakistani families with Usher syndrome IB.
Nonsyndromic Deafness
Liu et al. (1997) found mutations in the MYO7A gene in 2 of 8 families with autosomal recessive nonsyndromic deafness (DFNB2; 600060) from the Sichuan province of China. In 1 family, 3 affected sibs were homozygous for an R244P mutation (276903.0007).
In a Japanese family with autosomal dominant nonsyndromic hearing loss mapping to 11q (DFNA11; 601317), Liu et al. (1997) identified a heterozygous mutation in the MYO7A gene (276903.0011). All affected members of the family had postlingual bilateral sensorineural hearing loss with subsequent gradual progression. Luijendijk et al. (2004) identified a heterozygous mutation in the MYO7A gene (276903.0015) in affected members of a Dutch family with autosomal dominant nonsyndromic sensorineural deafness.
In affected members of a consanguineous Pakistani family with autosomal recessive DFNB2, Riazuddin et al. (2008) identified a homozygous mutation in the MYO7A gene (276903.0018).
In 3 sibs, born of consanguineous Iranian parents, with DFNB2, Hildebrand et al. (2010) identified a homozygous mutation in the MYO7A gene (R395H; 276903.0021).
Associations Pending Confirmation
In 4 affected members from a consanguineous Saudi Arabian family with Leber congenital amaurosis (LCA; see 204000), Wang et al. (2011) identified homozygosity for a missense mutation in the motor domain of the MYO7A gene (578C-T; T193I) that segregated with disease in the family and was not found in 200 controls or the dbSNP or 1000 Genomes Project databases. All 4 patients had poor vision since birth, with nystagmus, neuroepithelial atrophy, and nonrecordable electroretinograms. The authors stated that patients in this family did not exhibit hearing loss.
Digenic inheritance of nonsyndromic deafness had been presented by Balciuniene et al. (1998) in the case of a Swedish family whose affected members were carriers of DFNA2 (600101) and/or DFNA12 (601543), both autosomal dominant disorders. Increased severity of deafness was found in family members who were carriers of both alleles. Digenic inheritance was also suggested as one of the possible explanations in the case of DFNB15 (601869). Chen et al. (1997) observed this autosomal recessive nonsyndromic deafness in a family of Indian origin and found that it was linked to 2 loci, one on 3q and one on 19p. Adato et al. (1999) found this result interesting in relation to their work because one of the regions of linkage, 3q21.3-q25.2, included the USH3 locus, and the other, 19p13.3-p13.1, included among others the MYO1F gene (601480), which codes for another member of the unconventional myosin group.
Shaker-1 (sh1) homozygous mice show hyperactivity, head-tossing and circling due to vestibular dysfunction, as well as neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti. Gibson et al. (1995) described 3 different mutations in the Myo7a gene that segregated with the disorder in mice. All the mutations were located in the region encoding the myosin head. The sh1 phenotype differs from that of Usher syndrome in humans by the absence of retinal degeneration. Weil et al. (1995) noted that one form of human neurosensory recessive deafness without retinal dystrophy, DFNB2, maps to 11q in the same general region as USH1B and may represent the human equivalent of sh1.
Liu et al. (1998) demonstrated that mutant Myo7a causes defective distribution of melanosomes in the retinal pigment epithelium (RPE) of shaker-1 mice. Mutant Myo7a was targeted correctly in the RPE, but localization of melanosomes in the apical processes of these epithelial cells depended on proper Myo7A function. Thus, in the RPE, Myo7a has a function similar to that of myosin V (MYPO5A; 160777), another large unconventional myosin that is necessary for melanosome localization in the dendrites of melanocytes. Given the putative motor properties of Myo7a, it was plausible that melanosomes may be transported along the RPE apical processes as cargo of the molecule.
The zebrafish (Danio rerio) possesses 2 mechanosensory organs believed to be homologous to each other: the inner ear, which is responsible for the senses of audition and equilibrium, and the lateral line organ, which is involved in the detection of water movements. Eight zebrafish circler or auditory/vestibular mutants appear to have defects specific to sensory hair cell function. The circler genes may therefore encode components of the mechanotransduction apparatus and/or be the orthologous counterparts of the genes underlying human hereditary deafness. Ernest et al. (2000) determined that the phenotype of the circler mutant, mariner, is due to mutations in the zebrafish Myo7a homolog. Mariner sensory hair cells displayed morphologic and functional defects similar to those present in mouse shaker-1 hair cells. The findings demonstrated the striking conservation of the function of myosin VIIA throughout vertebrate evolution.
In studies of mouse photoreceptor cells with mutant Myo7a, Liu et al. (1999) presented evidence that myosin VIIa functions in the connecting cilium of photoreceptor cells and participates in the transport of opsin (RHO; 180380). The findings provided the first direct evidence that opsin travels along the connecting cilium en route to the outer segment and demonstrated that myosin may function in these cilium. Accordingly, abnormal opsin transport may contribute to blindness in Usher syndrome.
Boeda et al. (2001) generated lines of transgenic mice expressing the green fluorescent protein (GFP) reporter gene under the control of several 5-prime-truncated versions of the Myo7a/MYO7A promoter region and intron 1. They obtained transgenic mice with a GFP expression restricted to the hair cells of the inner ear, cochlea, and vestibule. Successive deletions of the promoter defined a minimal sequence of 118 bp that was sufficient, in the presence of intron 1, to target the transgene expression to hair cells. In addition, the deletion of intron 1 from the transgenes abolished hair cell expression, thus indicating the presence of a strong enhancer in the intron. The authors reported that regulatory sequences were sufficient to target the expression of a gene exclusively in sensory cells of the inner ear.
To elucidate the role of myosin VIIa in the retina and the basis of photoreceptor degeneration in USH1B patients, Gibbs et al. (2003) studied mutant phenotypes in the retinas of shaker-1 mice. They reported that the phagocytosis of photoreceptor outer segment discs by the RPE was abnormal in Myo7a-null mice. Both in vivo and in primary cultures of RPE cells, the transport of ingested discs out of the apical region was inhibited in the absence of Myo7a. The results with the cultured RPE cells were the same, irrespective of whether the discs came from wildtype or mutant mice, which demonstrated that the RPE is the source of this defect. The inhibited transport seemed to delay phagosome-lysosome fusion, as the degradation of ingested discs was slower in mutant RPE. Moreover, fewer packets of disc membranes were ingested in vivo, possibly because retarded removal of phagosomes from the apical processes inhibited the ingestion of additional disc membranes. Gibbs et al. (2003) concluded that myosin VIIa is required for the normal processing of ingested disc membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes. Because the phagocytosis of photoreceptor discs by the RPE had been shown to be critical for photoreceptor cell viability, the authors suggested that this defect likely contributes to the progressive blindness in USH1B.
The MYO15 (602666), MYO6 (600970), and MYO7A 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.
In affected members of a family with Usher syndrome type IB (USH1B; 276900), Weil et al. (1995) identified compound heterozygosity for 2 mutations in the MYO7A gene: a 163C-T transition in exon 1 resulting in an arg150-to-ter (R150X) substitution, and a 6-bp deletion (276903.0003). The R150X protein was predicted to be truncated before the ATP-binding site.
In affected members of a family with Usher syndrome type IB (USH1B; 276900), Weil et al. (1995) identified a heterozygous C-to-T transition in exon 3 of the MYO7A gene, resulting in a gln234-to-ter (Q234X) substitution and truncation of the protein before the actin-binding site.
In affected members of 2 unrelated families with Usher syndrome type IB (USH1B; 276900), Weil et al. (1995) identified the same in-frame 6-bp deletion (GACACT) in exon 3 of the MYO7A gene at codon 217, leading to loss of amino acid residues asp (D) and ile (I). In 1 family, the 2 affected brothers inherited the deletion mutation from their father and a nonsense mutation (276903.0001) from their mother. The 2 families originated from different geographic regions, suggesting that 2 independent mutational events were responsible for the 6-bp deletion. The deletion occurred in an 11-bp sequence containing two 5-bp direct repeats, and it was considered possible that either replication slippage or slipped-strand mispairing was responsible for the mutational event.
In individuals with Usher syndrome type IB (USH1B; 276900), Weil et al. (1995) identified a G-to-A transition in exon 7 of the MYO7A gene, resulting in an arg212-to-his (R212H) substitution.
Weston et al. (1996) stated that R212H and R212C (276903.0005) accounted for 8 of 23 mutant alleles from 20 probands in their study of USH1B. On 3 alleles (once in heterozygosity and once in homozygosity), the R212H mutation occurred in cis with an R302H (276903.0006) mutation in exon 9. Affected sibs in a Dutch family were homozygous for the double mutation at both codons, while the affected sibs in a Finnish family showed only paternal inheritance of both mutations. Both R302H and R212H were observed singly in affected persons; neither had been observed in controls, either singly or as double mutations. Although these 3 mutations were the most common ones observed, comprising approximately 50% of all mutations found, they still represented less than 3% of the total USH1B chromosomes studied. Furthermore, no linkage disequilibrium between USH1B and several adjacent polymorphic markers was found, suggesting that there are several independently occurring mutations rather than a common USH1B allele.
In affected members of a family segregating Usher syndrome type IB (USH1B; 276900), Weil et al. (1995) identified a C-to-T transition in exon 7 in the MYO&A gene, resulting in an arg212-to-cys (R212C; 276903.0005) substitution.
Weston et al. (1996) identified an arg302-to-his (R302H) mutation in the MYO7A gene in individuals with Usher syndrome type IB (USH1B; 276900), on 2 alleles in heterozygosity and on 3 alleles (once in heterozygosity and once in homozygosity) in cis with the R212H mutation (see 276903.0004). Both R302H and R212H were observed singly in affected persons; neither had been observed in controls, either singly or as double mutations.
Liu et al. (1997) found mutations in the MYO7A gene in 2 of 8 families with autosomal recessive nonsyndromic deafness (DFNB2; 600060) from the Sichuan province of China. In 1 family, 3 affected sibs were homozygous for an arg244-to-pro (R244P) substitution.
Riazuddin et al. (2008) stated that the R244P mutation is located in the motor domain of the protein. In vitro studies with the mouse ortholog, R233P, showed that the mutant protein did not localize within stereocilia of hair cells, similar to that observed with MYO7A constructs corresponding to Usher syndrome IB (USH1B; 276900) mutants. Although R233P showed normal affinity to actin filaments, the ATPase rate was decreased compared to wildtype.
In a Chinese family with nonsyndromic autosomal recessive deafness (DFNB2; 600060), Liu et al. (1997) found that 2 sibs were compound heterozygous for an acceptor splice site mutation in intron 3 (IVS3-2A-G) in 1 allele, while the other allele carried a T insertion in exon 28 (276903.0009), val1199insT(fs), leading to a frameshift and stop codon 28 amino acids downstream.
For discussion of the T insertion in exon 28 of the MYO7A gene that was found in compound heterozygous state in a Chinese family with nonsyndromic autosomal recessive deafness (DFNB2; 600060) by Liu et al. (1997), see 276903.0008.
In affected members of a large consanguineous family from Tunisia in which 22 members were originally reported to have autosomal recessive sensorineural deafness (DFNB2; 600060) (Guilford et al., 1994), Weil et al. (1997) identified a homozygous G-to-A transition at the last nucleotide of exon 15 in the MYO7A gene, resulting in a met599-to-ile (M599I) substitution. The mutation was not detected in 100 unaffected individuals living in the same Tunisian region who were not related to the affected family.
Zina et al. (2001) reevaluated the family reported by Guilford et al. (1994) and Weil et al. (1997). Since the original reports, 5 patients had developed mild retinal degeneration in addition to the progressive deafness. Fundus examination of 1 patient showed spicule pigmentary changes consistent with retinal dystrophy. Another previously unaffected family member, homozygous for the mutation, had retinitis pigmentosa. Seven patients had abnormal vestibular function as assessed by caloric tests. Zina et al. (2001) concluded that some patients in this Tunisian family had features consistent with Usher syndrome type IB (USH1B; 276900). The findings suggested that other factors must modulate the expression of the phenotype.
In a Japanese family with autosomal dominant nonsyndromic hearing loss mapping to 11q (DFNA11; 601317), Liu et al. (1997) demonstrated an in-frame 9-bp deletion in exon 22 of the MYO7A gene, leading to deletion of 3 amino acids (ala886-lys887-lys888) in the coiled-coil region of the protein. All affected members of the family had postlingual bilateral sensorineural hearing loss with subsequent gradual progression. This was the first mutation identified in the coiled-coiled region, which is thought to be responsible for dimerization of the molecule. Liu et al. (1997) postulated that the mutant protein interacted with the wildtype protein, resulting in a dominant-negative effect.
In 3 affected members of a Spanish family with Usher syndrome type IB (USH1B; 276900), Cuevas et al. (1998) identified a homozygous C-to-A transversion in exon 16 of the MYO7A gene, resulting in a cys628-to-ter (C682X) substitution. The mutation segregated with the phenotype in the family.
In 9 of 12 mutant alleles in 6 patients from Denmark with Usher syndrome type IB (USH1B; 276900), Janecke et al. (1999) identified a C-to-A transversion in exon 3 of the MYO7A gene, resulting in a cys31-to-ter (C31X) substitution. Although the families were not known to be related, genotyping for 6 intragenic polymorphisms suggested that the 9 mutation-bearing chromosomes originated from the same ancestor. Weston et al. (1996) had detected the same C31X mutation in a proband from Sweden and in a proband of Scandinavian ancestry from the United States.
This variant is classified as a variant of unknown significance because its contribution to Usher syndrome has not been confirmed.
Adato et al. (1999) suggested that digenic inheritance might be operative in a Yemenite family in which 2 of 8 children had Usher syndrome. Two affected brothers in this family had different Usher syndrome phenotypes. One had a typical USH1 phenotype (276900): he had a history of prelingual profound auditory impairment; he used sign language for communication, since hearing aids were unhelpful in his case; and developmental milestones in his childhood were consistent with congenital vestibular dysfunction. The other affected brother had a typical USH3 phenotype (276902): he had progressive hearing loss, with postlingual onset; he used hearing aids and verbal communication; and he received psychiatric therapy for mental problems. Both brothers had bilateral progressive pigmentary retinopathy, with onset during early adolescence. In both affected brothers, Adato et al. (1999) found homozygosity for a haplotype consistent with a location on chromosome 3, where the USH3 gene is located. Since one of the affected brothers had a USH1 phenotype, family members were screened for mutations in the MYO7A gene. On 1 maternal chromosome, transmitted to the brother with the USH1 phenotype and to 2 unaffected sibs, but not to the brother with the USH3 phenotype, they found a double mutation: a T-to-C transition in exon 25 of the MYO7A gene, predicted to cause a leu1087-to-pro (L1087P) substitution; and a guanine deletion 5 nucleotides upstream of this transition, predicted to cause a frameshift of the reading frame starting at codon 1089. This frameshift would result in the formation of a UGA stop codon 18 amino acids downstream from the deletion site and, therefore, in the translation of a truncated protein that lacked more than 50% of its normal amino acid sequence, which comprises most of the MYO7A tail domain. Segregation of the mutated MYO7A with healthy family members as well as with the more severe USH phenotype suggested a possible biologic interaction between MYO7A and the USH3 gene products. The mutated MYO7A appeared to be phenotypically expressed only on the background of 2 USH3 alleles. Adato et al. (2002) restudied the Jewish Yemenite family previously reported by Adato et al. (1999) and identified homozygosity for a 23-bp deletion in the CLRN1 gene (606397.0007) in the affected brothers. The authors stated that this represented a departure from the monogenic model for Usher syndrome.
In affected members of a Dutch family with autosomal dominant nonsyndromic sensorineural deafness (DFNA11; 601317), Luijendijk et al. (2004) identified a heterozygous 1373A-T transversion in exon 13 of the MYO7A gene, resulting in an asn458-to-ile (N458I) substitution. In a molecular model, the mutant protein was predicted to disrupt ATP binding and impair the myosin power stroke.
Through a systematic mutation screening of the genes known to cause type I Usher syndrome in patients from the U.S. and U.K., Ouyang et al. (2005) identified a 1996C-T transition in exon 17 of the MYO7A gene, resulting in an arg666-to-ter nonsense mutation (R666X). The mutation was predicted to truncate myosin VIIA by approximately 90%. Of the 12 mutations detected by Ouyang et al. (2005) at the MYO7A locus in patients with type I Usher syndrome (USH1B; 276900), 5 of 21 alleles (23.8%) were R666X. A G-C transversion within the splice acceptor site of intron 27 (276903.0017) accounted for 3 of 21 alleles (14.3%).
Of the 12 mutations detected by Ouyang et al. (2005) at the MYO7A locus in patients with type I Usher syndrome (USH1B; 276900), a G-C transversion within the splice acceptor site of intron 27 accounted for 3 of 21 alleles (14.3%).
In affected members of a consanguineous Pakistani family with autosomal recessive deafness (DFNB2; 600060), Riazuddin et al. (2008) identified a homozygous 3-bp deletion (5146delGAG) in exon 37 of the MYO7A gene, resulting in an in-frame loss of a conserved glutamate residue at codon 1716. This residue is located in the tail region between the SH3 domain and the second MyTH4 domain. In vitro studies targeting the homologous mutant 5146delGAG protein in cultured mouse cells indicated that the protein localized along the length of inner ear hair cell stereocilia similar to the wildtype protein. Similar studies with truncating MYO7A mutations resulting in Usher syndrome IB (USH1B; 276900) showed no localization to stereocilia. Riazuddin et al. (2008) concluded that the mutation in this family caused a less severe phenotype compared to that of Usher syndrome IB because of residual protein function.
In affected members of a Chinese family with autosomal dominant nonsyndromic deafness-11 (DFNA11; 601317), Sun et al. (2011) identified a heterozygous 652G-A transition in exon 7 of the MYO7A gene, resulting in an asp218-to-asn (D218N) substitution in a conserved residue in the motor domain. The mutation was not found in 100 controls. Affected individuals had onset between ages 20 and 47 years of bilateral mild to severe symmetric hearing impairment particularly involving high frequencies. The audiogram was flat or downward sloping. Tinnitus occurred before hearing loss, but there was no vestibular involvement.
In affected members of a Chinese family with autosomal dominant nonsyndromic deafness-11 (DFNA11; 601317), Sun et al. (2011) identified a heterozygous 2011G-A transition in exon 17 of the MYO7A gene, resulting in a gly671-to-ser (G671S) substitution in a conserved residue in the region of the myosin head converter domain. Affected individuals had onset between ages 10 and 39 years of bilateral mild to severe symmetric hearing loss affecting mainly low frequencies. The audiogram was flat or ascending. Tinnitus occurred before hearing loss, but there was no vestibular involvement. Electrocochleography in this family showed no evidence of endolymphatic hydrops. Molecular modeling suggested that the substituted serine side chain projects into a conserved hydrophobic pocket in the converter domain and relay loop of this region, generating steric hindrance with neighboring amino acid tyr477.
In 3 sibs, born of consanguineous Iranian parents, with autosomal recessive deafness-2 (DFNB2; 600060), Hildebrand et al. (2010) identified a homozygous 1184G-A transition in exon 11 of the MYO7A gene, resulting in an arg395-to-his (R395H) substitution in a highly conserved residue in the motor domain of the protein. The mutation was not found in 94 Iranian control chromosomes or in 258 control chromosomes. Onset of hearing loss occurred between ages 7 months and 7 years. Audiologic testing revealed hearing loss at all frequencies, although low frequency hearing was less impaired. All had normal vestibular function, and funduscopic examination and visual acuity tests excluded retinitis pigmentosa in all patients at ages 39, 31, and 42 years, respectively. One patient had a milder phenotype, with later onset and less severe impairment, suggesting the presence of a genetic modifier. The findings confirmed that nonsyndromic hearing loss can be caused by mutation in the MYO7A gene.
Adato, A., Kalinski, H., Weil, D., Chaib, H., Korostishevsky, M., Bonne-Tamir, B. Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. (Letter) Am. J. Hum. Genet. 65: 261-265, 1999. [PubMed: 10364543] [Full Text: https://doi.org/10.1086/302438]
Adato, A., Vreugde, S., Joensuu, T., Avidan, N., Hamalainen, R., Belenkiy, O., Olender, T., Bonne-Tamir, B., Ben-Asher, E., Espinos, C., Millan, J. M., Lehesjoki, A.-E., Flannery, J. G., Avraham, K. B., Pietrovski, S., Sankila, E.-M., Beckmann, J. S., Lancet, D. USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. Europ. J. Hum. Genet. 10: 339-350, 2002. [PubMed: 12080385] [Full Text: https://doi.org/10.1038/sj.ejhg.5200831]
Adato, A., Weil, D., Kalinski, H., Pel-Or, Y., Ayadi, H., Petit, C., Korostishevsky, M., Bonne-Tamir, B. Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins. Am. J. Hum. Genet. 61: 813-821, 1997. [PubMed: 9382091] [Full Text: https://doi.org/10.1086/514899]
Bahloul, A., Michel, V., Hardelin, J.-P., Nouaille, S., Hoos, S., Houdusse, A., England, P., Petit, C. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, for a ternary complex and interact with membrane phospholipids. Hum. Molec. Genet. 19: 3557-3565, 2010. [PubMed: 20639393] [Full Text: https://doi.org/10.1093/hmg/ddq271]
Balciuniene, J., Dahl, N., Borg, E., Samuelsson, E., Koisti, M. J., Pettersson, U., Jazin, E. E. Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family. Am. J. Hum. Genet. 63: 786-793, 1998. [PubMed: 9718342] [Full Text: https://doi.org/10.1086/302012]
Boeda, B., El-Amraoui, A., Bahloul, A., Goodyear, R., Daviet, L., Blanchard, S., Perfettini, I., Fath, K. R., Shorte, S., Reiners, J., Houdusse, A., Legrain, P., Wolfrum, U., Richardson, G., Petit, C. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 21: 6689-6699, 2002. [PubMed: 12485990] [Full Text: https://doi.org/10.1093/emboj/cdf689]
Boeda, B., Weil, D., Petit, C. A specific promoter of the sensory cells of the inner ear defined by transgenesis. Hum. Molec. Genet. 10: 1581-1589, 2001. [PubMed: 11468276] [Full Text: https://doi.org/10.1093/hmg/10.15.1581]
Chen, A., Wayne, S., Bell, A., Ramesh, A., Srisailapathy, C. R., Scott, D. A., Sheffield, V. C., Van Hauwe, P., Zbar, R. I., Ashley, J., Lovett, M., Van Camp, G., Smith, R. J. New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p. Am. J. Med. Genet. 71: 467-471, 1997. [PubMed: 9286457]
Chen, Z.-Y., Hasson, T., Kelley, P. M., Schwender, B. J., Schwartz, M. F., Ramakrishnan, M., Kimberling, W. J., Mooseker, M. S., Corey, D. P. Molecular cloning and domain structure of human myosin-VIIa, the gene product defective in Usher syndrome 1B. Genomics 36: 440-448, 1996. [PubMed: 8884267] [Full Text: https://doi.org/10.1006/geno.1996.0489]
Cuevas, J. M., Espinos, C., Millan, J. M., Sanchez, F., Trujillo, M. J., Garcia-Sandoval, B., Ayuso, C., Najera, C., Beneyto, M. Detection of a novel cys628-to-stop mutation of the myosin VIIA gene in Usher syndrome type Ib. Molec. Cell. Probes 12: 417-420, 1998. [PubMed: 9843659] [Full Text: https://doi.org/10.1006/mcpr.1998.0202]
El-Amraoui, A., Sahly, I., Picaud, S., Sahel. J., Abitbol, M., Petit, C. Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells. Hum. Molec. Genet. 5: 1171-1178, 1996. [PubMed: 8842737] [Full Text: https://doi.org/10.1093/hmg/5.8.1171]
Ernest, S., Rauch, G.-J., Haffter, P., Geisler, R., Petit, C., Nicolson, T. Mariner is defective in myosin VIIA: a zebrafish model for human hereditary deafness. Hum. Molec. Genet. 9: 2189-2196, 2000. [PubMed: 10958658] [Full Text: https://doi.org/10.1093/hmg/9.14.2189]
Gibbs, D., Kitamoto, J., Williams, D. S. Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proc. Nat. Acad. Sci. 100: 6481-6486, 2003. [PubMed: 12743369] [Full Text: https://doi.org/10.1073/pnas.1130432100]
Gibson, F., Walsh, J., Mburu, P., Varela, A., Brown, K. A., Antonio, M., Beisel, K. W., Steel, K. P., Brown, S. D. M. A type VII myosin encoded by the mouse deafness gene shaker-1. Nature 374: 62-64, 1995. [PubMed: 7870172] [Full Text: https://doi.org/10.1038/374062a0]
Guilford, P., Ayadi, H., Blanchard, S., Chaib, H., Le Paslier, D., Weissenbach, J., Drira, M., Petit, C. A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum. Molec. Genet. 3: 989-993, 1994. [PubMed: 7951250] [Full Text: https://doi.org/10.1093/hmg/3.6.989]
Hildebrand, M. S., Thorne, N. P., Bromhead, C. J., Kahrizi, K., Webster, J. A., Fattahi, Z., Bataejad, M., Kimberling, W. J., Stephan, D., Najmabadi, H., Bahlo, M., Smith, R. J. H. Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation. Clin. Genet. 77: 563-571, 2010. [PubMed: 20132242] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01344.x]
Janecke, A. R., Meins, M., Sadeghi, M., Grundmann, K., Apfelstedt-Sylla, E., Zrenner, E., Rosenberg, T., Gal, A. Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. Hum. Mutat. 13: 133-140, 1999. [PubMed: 10094549] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<133::AID-HUMU5>3.0.CO;2-U]
Karolyi, I. J., Probst, F. J., Beyer, L., Odeh, H., Dootz, G., Cha, K. B., Martin, D. M., Avraham, K. B., Kohrman, D., Dolan, D. F., Raphael, Y., Camper, S. A. Myo15 function is distinct from Myo6, Myo7a and pirouette genes in development of cochlear stereocilia. Hum. Molec. Genet. 12: 2797-2805, 2003. [PubMed: 12966030] [Full Text: https://doi.org/10.1093/hmg/ddg308]
Kelley, P. M., Weston, M. D., Chen, Z.-Y., Orten, D. J., Hasson, T., Overbeck, L. D., Pinnt, J., Talmadge, C. B., Ing, P., Mooseker, M. S., Corey, D., Sumegi, J., Kimberling, W. J. The genomic structure of the gene defective in Usher syndrome type Ib (MYO7A). Genomics 40: 73-79, 1997. [PubMed: 9070921] [Full Text: https://doi.org/10.1006/geno.1996.4545]
Levy, G., Levi-Acobas, F., Blanchard, S., Gerber, S., Larget-Piet, D., Chenal, V., Liu, X.-Z., Newton, V., Steel, K. P., Brown, S. D. M., Munnich, A., Kaplan, J., Petit, C., Weil, D. Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. Hum. Molec. Genet. 6: 111-116, 1997. [PubMed: 9002678] [Full Text: https://doi.org/10.1093/hmg/6.1.111]
Liu, X., Ondek, B., Williams, D. S. Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice. (Letter) Nature Genet. 19: 117-118, 1998. [PubMed: 9620764] [Full Text: https://doi.org/10.1038/470]
Liu, X., Udovichenko, I. P., Brown, S. D. M., Steel, K. P., Williams, D. S. Myosin VIIa participates in opsin transport through the photoreceptor cilium. J. Neurosci. 19: 6267-6274, 1999. [PubMed: 10414956] [Full Text: https://doi.org/10.1523/JNEUROSCI.19-15-06267.1999]
Liu, X.-Z., Walsh, J., Mburu, P., Kendrick-Jones, J., Cope, M. J. T. V., Steel, K. P., Brown, S. D. M. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nature Genet. 16: 188-190, 1997. [PubMed: 9171832] [Full Text: https://doi.org/10.1038/ng0697-188]
Liu, X.-Z., Walsh, J., Tamagawa, Y., Kitamura, K., Nishizawa, M., Steel, K. P., Brown, S. D. M. Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. (Letter) Nature Genet. 17: 268-269, 1997. [PubMed: 9354784] [Full Text: https://doi.org/10.1038/ng1197-268]
Luijendijk, M. W. J., van Wijk, E., Bischoff, A. M. L. C., Krieger, E., Huygen, P. L. M., Pennings, R. J. E., Brunner, H. G., Cremers, C. W. R. J., Cremers, F. P. M., Kremer, H. Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11). Hum. Genet. 115: 149-156, 2004. [PubMed: 15221449] [Full Text: https://doi.org/10.1007/s00439-004-1137-3]
Ouyang, X. M., Yan, D., Du, L. L., Hejtmancik, J. F., Jacobson, S. G., Nance, W. E., Li, A. R., Angeli, S., Kaiser, M., Newton, V., Brown, S. D. M., Balkany, T., Liu, X. Z. Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum. Genet. 116: 292-299, 2005. [PubMed: 15660226] [Full Text: https://doi.org/10.1007/s00439-004-1227-2]
Riazuddin, S., Nazli, S., Ahmed, Z. M., Yang, Y., Zulfiqar, F., Shaikh, R. S., Zafar, A. U., Khan, S. N., Sabar, F., Javid, F. T., Wilcox, E. R., Tsilou, E., Boger, E. T., Sellers, J. R., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum. Mutat. 29: 502-511, 2008. [PubMed: 18181211] [Full Text: https://doi.org/10.1002/humu.20677]
Sun, Y., Chen, J., Sun, H., Cheng, J., Li, J., Lu, Y., Lu, Y., Jin, Z., Zhu, Y., Ouyang, X., Yan, D., Dai, P., Han, D., Yang, W., Wang, R., Liu, X., Yuan, H. Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China. J. Hum. Genet. 56: 64-70, 2011. [PubMed: 21150918] [Full Text: https://doi.org/10.1038/jhg.2010.147]
Wang, X., Wang, H., Cao, M., Li, Z., Chen, X., Patenia, C., Gore, A., Abboud, E. B., Al-Rajhi, A. A., Lewis, R. A., Lupski, J. R., Mardon, G., Zhang, K., Muzny, D., Gibbs, R. A., Chen, R. Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum. Mutat. 32: 1450-1459, 2011. [PubMed: 21901789] [Full Text: https://doi.org/10.1002/humu.21587]
Weil, D., Blanchard, S., Kaplan, J., Guilford, P., Gibson, F., Walsh, J., Mburu, P., Varela, A., Levilliers, J., Weston, M. D., Kelley, P. M., Kimberling, W. J., Wagenaar, M., Levi-Acobas, F., Larget-Piet, D., Munnich, A., Steel, K. P., Brown, S. D. M., Petit, C. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374: 60-61, 1995. [PubMed: 7870171] [Full Text: https://doi.org/10.1038/374060a0]
Weil, D., Kussel, P., Blanchard, S., Levy, G., Levi-Acobas, F., Drira, M., Ayadi, H., Petit, C. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nature Genet. 16: 191-193, 1997. [PubMed: 9171833] [Full Text: https://doi.org/10.1038/ng0697-191]
Weil, D., Levy, G., Sahly, I., Levi-Acobas, F., Blanchard, S., El-Amraoui, A., Crozet, F., Philippe, H., Abitbol, M., Petit, C. Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. Proc. Nat. Acad. Sci. 93: 3232-3237, 1996. [PubMed: 8622919] [Full Text: https://doi.org/10.1073/pnas.93.8.3232]
Weston, M. D., Kelley, P. M., Overbeck, L. D., Wagenaar, M., Orten, D. J., Hasson, T., Chen, Z.-Y., Corey, D., Mooseker, M., Sumegi, J., Cremers, C., Moller, C., Jacobson, S. G., Gorin, M. B., Kimberling, W. J. Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. Am. J. Hum. Genet. 59: 1074-1083, 1996. [PubMed: 8900236]
Wu, L., Pan, L., Wei, Z., Zhang, M. Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. Science 331: 757-760, 2011. [PubMed: 21311020] [Full Text: https://doi.org/10.1126/science.1198848]
Zina, Z., Masmoudi, S., Ayadi, H., Chaker, F., Ghorbel, A. M., Drira, M., Petit, C. From DFNB2 to Usher syndrome: variable expressivity of the same disease. (Letter) Am. J. Med. Genet. 101: 181-183, 2001. [PubMed: 11391666] [Full Text: https://doi.org/10.1002/ajmg.1335]