Disease relevance of Myo7a

• Because the mutant Cdh23 phenotype was found to be similar to the previously reported retinal phenotype of Myo7a mutant mice, the orthologue of another Usher syndrome (type 1B) gene, we generated mice that carried mutations in both genes to test for genetic interaction in the retina [1].
• Progressive hearing loss and increased susceptibility to noise-induced hearing loss in mice carrying a Cdh23 but not a Myo7a mutation [2].
• Noise-induced hearing loss in 11-12-week-old mice heterozygous for a null allele of Myo7a ( Myo7a(4626SB)) is not significantly different from wild-type littermates [2].

High impact information on Myo7a

• Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice [3].
• Recently, it has been shown that a gene encoding an unconventional myosin, myosin VIIA, underlies the mouse recessive deafness mutation, shaker-1 (ref. 5) as well as Usher syndrome type 1b [4].
• The sh1 gene encodes an unconventional myosin molecule of the type VII family [5].
• Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations [6].
• In stereocilia, constructed of cross-linked F-actin filaments, myosin-Ibeta is found mostly near stereociliary tips, myosin-VI is largely absent, and myosin-VIIa colocalizes with crosslinks that connect adjacent stereocilia [7].

Biological context of Myo7a

• Here, we report that the phagocytosis of photoreceptor outer segment disks by the retinal pigment epithelium (RPE) is abnormal in Myo7a null mice [8].
• We generated lines of transgenic mice expressing the green fluorescent protein (GFP ) reporter gene under the control of several 5'-truncated versions of the Myo7a/MYO7A promoter region and intron 1 [9].
• The headbanger mutation has been mapped to a 1.5-cM region on mouse Chromosome 7 in the region of the unconventional myosin gene Myo7a, and mutation screening revealed an A>T transversion that is predicted to cause an isoleucine-to-phenylalanine amino acid substitution (I178F) in a conserved region in the motor-encoding domain of the gene [10].
• Haplotype analysis indicates that Omp lies proximal to sh-1 [11].
• One thousand eight mice were analyzed for a restriction fragment length polymorphism segregating for the proximal flanking marker, tyrosinase (c), and 54 recombinants between c and sh-1 were identified, completing a panel of 67 recombinant mice from the backcross in the vicinity of the sh-1 mutation [11].

Anatomical context of Myo7a

• In RPE cells from Myo7a-null mice, both the slow and rapid movements still occurred, except that more melanosomes underwent rapid movements, and each movement extended approximately five times longer (and further) [12].
• In mice with mutant Myo7a, melanosomes in the retinal pigmented epithelium (RPE) are distributed abnormally [12].
• Myo7a was expressed normally in the hair cells of P0 Cdh23(v2J) mutants demonstrating that cadherin 23 is not required for Myo7a expression at this stage [13].
• We conclude that Myo7a is required for the normal processing of ingested disk membranes in the RPE, primarily in the basal transport of phagosomes into the cell body where they then fuse with lysosomes [8].
• In sh-1 homozygotes this deafness is associated with neurophysiological abnormalities that may be accompanied by structural abnormalities of the inner ear [14].

Associations of Myo7a with chemical compounds

• Transgenic analyses have revealed the presence of hair-cell-specific promoters in the genes encoding Math1, myosin VIIa, Pou4f3, and the alpha9 subunit of the acetylcholine receptor (alpha9 AChR) [15].
• Myosin VIIa Mg-ATPase activity was detected; in the absence of Ca(2+) (i.e. with bound calmodulin), it was stimulated by f-actin with a K(cat) of 4.3 s(-1) and with 7 microM actin required for half-maximal activity [16].
• Our studies demonstrate that harmonin and myosin VIIa are not localized in the same compartments in the mouse and human retinas, indicating that they do not interact in this organ, contrary to what has been shown in the inner ear [17].
• Hair cells from homozygous mutant Myo7ash1 mice, with a mutation in a nonconserved region of the myosin VIIA head, respond rapidly to aminoglycoside treatment and accumulate high levels of gentamicin [18].

Physical interactions of Myo7a

• Notably, whirlin also interacts with myosin VIIa that is present along the entire length of the stereocilia [19].
• We found evidence that myosin VIIa functions in the connecting cilium of each photoreceptor cell and participates in the transport of opsin through this structure [20].

Regulatory relationships of Myo7a

• Under differentiating culture conditions, transfected E-cadherin inhibited expression of the cytoskeletal protein myosin VIIa and functional expression of both acetylcholine receptors and potassium channels, which are normally expressed by neonatal hair cells [21].

Other interactions of Myo7a

• These data suggest that the function of Myo15 is distinct from that of Myo6, Myo7a or pi in development and/or maintenance of stereocilia [22].
• Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes [12].
• One thousand fifty-two mice were analyzed for a protein polymorphism segregating for the distal flanking marker, beta-globin (Hbb), and 13 recombinants between Hbb and sh-1 were identified [11].
• In the cuticular plate, a meshwork of actin filaments, myosin-Ibeta is excluded, myosin-VI is concentrated, and modest amounts of myosin-VIIa are present [7].
• Complementation analysis provided evidence for a true repeat mutation at the sh-1 (shaker-1) locus (for the neurological mutations) and another at the here defined fit-1 (fitness-1) locus [23].

Analytical, diagnostic and therapeutic context of Myo7a

• Some 70-80% of the myosin VIIa in RPE cells was detected on melanosome membranes by both subcellular fractionation of RPE cells and quantitative immunoelectron microscopy, consistent with a role for myosin VIIa in melanosome motility [12].
• Myosin VIIA is therefore required for the normal gating of transducer channels [6].
• Here, we studied the photoreceptor cells of mice with mutant myosin VIIa by electron immunomicroscopy and microscopic autoradiography [20].
• Mice, 3-, 6-, 10-, 12-, 18-, and 30 days old, homozygous for the sh-1 gene, were studied using transmission electron microscopy [24].
• Northern blot analysis indicated that myosin-VIIa mRNA expression, size, and stability were unaffected in the seven sh1 alleles [25].

References