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Query: UMLS:C0011053 (deafness)
 10,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic hearing impairment affects around 1 in every 2,000 births. The bulk (approximately 70%) of genetic deafness is non-syndromic, in which hearing impairment is not associated with any other abnormalities. Over 25 loci involved in non-syndromic deafness have been mapped and mutations in connexin 26 have been identified as a cause of non-sydromic deafness. One locus for non-syndromic recessive deafness, DFNB2 (ref. 4), has been localized to the same chromosomal region, 11q14, as one of the loci, USH1B, underlying the recessive deaf-blind syndrome. Usher syndrome type 1b, which is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. 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. Mice with shaker-1 demonstrate typical neuroepithelial defects manifested by hearing loss and vestibular dysfunction but no retinal pathology. Differences in retinal patterns of expression may account for the variance in phenotype between shaker-1 mice and Usher type 1 syndrome. Nevertheless, the expression of MYO7A in the neuroepithelium suggests that it should be considered a candidate for non-syndromic deafness in the human population. By screening families with non-syndromic deafness from China, we have identified two families carrying MYO7A mutations.
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PMID:Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. 917 32

Hereditary non-syndromic profound deafness affects about 1 in 2000 children prior to language acquisition. In 80% of the cases, the mode of transmission is autosomal recessive. The number of genes involved in these recessive forms of isolated deafness (DFNB genes) has been estimated to between 30 and 100. So far, ten DFNB genes have been mapped to human chromosomes, one of which has been isolated. By linkage analysis of a single family whose members were affected with profound deafness, some of them presenting with vestibular dysfunction, DFNB2 has been mapped to chromosome 11q13 (ref. 3). The gene responsible for a form of Usher syndrome type I, USH1B, has been assigned to the same chromosomal region. Usher syndrome associates profound congenital deafness and vestibular dysfunction with retinitis pigmentosa. In the homologous murine region are located the shaker-1 mutations responsible for deafness and vestibular dysfunction. It has been demonstrated that the murine shaker-1 and human USH1B phenotypes result from mutations in the gene encoding myosin-VIIA. Based on mapping data as well as on the similarities between the phenotypes of DFNB2-affected patients and shaker-1 mouse mutants, we have proposed that a defective myosin-VIIA may also be responsible for DFNB2 (ref. 1). Sequence analysis of each of the coding exons of the myosin-VIIA gene (MYO7A) was thus undertaken in the DFNB2-affected family. In the last nucleotide of exon 15, a G to A transition was detected, a type of mutation that is known to decrease the efficiency of splicing. Accordingly, this result shows that different mutations in MYO7A result in either an isolated or a syndromic form of deafness.
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PMID:The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. 917 33

Numerous mammalian diseases have been found to be due to mutations in components of the actin cytoskeleton. Recently, mutations in the gene for an unconventional myosin, myosin-VIIa, were found to be the basis for the deafness and vestibular dysfunction observed in shaker-1 (sh1) mice and for a human deafness-blindness syndrome, Usher syndrome type 1B. Seven alleles of sh1 mice were analyzed to assess the affects of different myosin-VIIa mutations on both gene expression and tissue function. Myosin-VIIa is expressed in the inner ear and the retina, as well as the kidney, lung, and testis. Northern blot analysis indicated that myosin-VIIa mRNA expression, size, and stability were unaffected in the seven sh1 alleles. Immunoblot analysis showed that all seven alleles expressed some full-length myosin-VIIa protein. The range of expression, however, ran from sh1 [original], which expressed wild-type levels of protein, to two strains, sh1(4494SB) and sh1(4626SB), which expressed less than 1% of the normal level of myosin-VIIa protein. For the three alleles of sh1 that have been characterized and that have mutations in the motor domain, sh1 [original], sh1(816SB) and sh1(6J), the level of protein expression observed in these sh1 alleles correlated well with the predicted effects of the mutations on motor function. No change in retinal or testicular structure was observed at the light microscopic level during the life span of the seven sh1 alleles. Myosin-VIIa protein, when detectable, was observed to locate properly in the sh1 mice. On the basis of these results, we propose that the mutations in myosin-VIIa in the sh1 alleles leads to both motor dysfunction and to a protein destabilization phenotype.
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PMID:Effects of shaker-1 mutations on myosin-VIIa protein and mRNA expression. 918 10

Usher syndrome is the most common form of combined deafness and blindness. The gene that is defective in Usher syndrome 1B (USH1B) encodes for an unconventional myosin, myosin VIIa. To understand the cellular function of myosin VIIa and why defects in it lead to USH1B, it is essential to determine the precise cellular and subcellular localization of the protein. We investigated the distribution of myosin VIIa in human and rodent photoreceptor cells and retinal pigment epithelium (RPE), primarily by immunoelectron microscopy, using antibodies generated against two different domains of the protein. In both human and rodent retinae, myosin VIIa was detected in the apical processes of the RPE and in the cilium of rod and cone photoreceptor cells. Immunogold label was most concentrated in the connecting cilium. Here, myosin VIIa appeared to be distributed outside the ring of doublet microtubules near the ciliary plasma membrane. These observations indicate that a major role of myosin VIIa in the retina is in the photoreceptor cilium, perhaps in such a function as trafficking newly synthesized phototransductive membrane or maintaining the diffusion barrier between the inner and outer segments. Our results support the notion that defective ciliary function is the underlying cellular abnormality that leads to cellular degeneration in Usher syndrome.
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PMID:Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells. 922 54

Deafness is the most common form of sensory impairment in humans. Mutations in unconventional myosins have been found to cause deafness in humans and mice. The mouse recessive deafness mutation, Snell's waltzer, contains an intragenic deletion in an unconventional myosin, myosin VI (locus designation, Myo6). The requirement for Myo6 for proper hearing in mice makes this gene an excellent candidate for a human deafness disorder. Here we report the cloning and characterization of the human unconventional myosin VI (locus designation, MYO6) cDNA. The MYO6 gene maps to human chromosome 6q13. The isolation of the human gene makes it now possible to determine if mutations in MYO6 contribute to the pathogenesis of deafness in the human population.
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PMID:Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice. 925 67

The gene encoding myosin VIIA is responsible for the mouse shaker-1 phenotype, which consists of deafness and balance deficiency related to cochlear and vestibular neuroepithelial defects. In humans, a defective myosin VIIA gene is responsible for Usher syndrome type IB, which associates congenital deafness, vestibular dysfunction and retinitis pigmentosa. In an attempt to progress in the understanding of the function(s) of myosin VIIA, we studied the expression of the myosin VIIA gene during mouse embryonic development. Embryos from day 9 (E9) to E18 were analyzed by in situ hybridization and immunohistofluorescence. The myosin VIIA mRNA and protein were consistently detected in the same embryonic tissues throughout development. Myosin VIIA was first observed in the otic vesicle at E9, and later in a variety of tissues. The olfactory epithelium and the liver express it as early as E10. In the retinal pigment epithelium, choroid plexus, adrenal gland and tongue, expression begins at E12 and in the testis and the adenohypophysis at E13. In the small intestine, kidney and hair follicles of the vibrissae, expression of myosin VIIA starts only at E15. Myosin VIIA expression was observed only in epithelial cell types, most of which possess microvilli or cilia. Interestingly, myosin VIIA expression seems to be concomitant with the appearance of these structures in the epithelial cells, suggesting a role for this myosin in their morphogenesis. The cellular location of myosin VIIA within sensory hair cells and olfactory receptor neurons also argues for a role of this protein in the synaptic vesicle trafficking.
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PMID:Expression of myosin VIIA during mouse embryogenesis. 927 60

The shaker-2 mouse mutation, the homolog of human DFNB3, causes deafness and circling behavior. A bacterial artificial chromosome (BAC) transgene from the shaker-2 critical region corrected the vestibular defects, deafness, and inner ear morphology of shaker-2 mice. An unconventional myosin gene, Myo15, was discovered by DNA sequencing of this BAC. Shaker-2 mice were found to have an amino acid substitution at a highly conserved position within the motor domain of this myosin. Auditory hair cells of shaker-2 mice have very short stereocilia and a long actin-containing protrusion extending from their basal end. This histopathology suggests that Myo15 is necessary for actin organization in the hair cells of the cochlea.
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PMID:Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. 963 18

DFNB3, a locus for nonsyndromic sensorineural recessive deafness, maps to a 3-centimorgan interval on human chromosome 17p11.2, a region that shows conserved synteny with mouse shaker-2. A human unconventional myosin gene, MYO15, was identified by combining functional and positional cloning approaches in searching for shaker-2 and DFNB3. MYO15 has at least 50 exons spanning 36 kilobases. Sequence analyses of these exons in affected individuals from three unrelated DFNB3 families revealed two missense mutations and one nonsense mutation that cosegregated with congenital recessive deafness.
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PMID:Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. 963 18

The shaker-1 (Myo7a) mouse deafness locus is encoded by an unconventional myosin gene: myosin VIIA [Gibson, Walsh, Mburu, Varela, Brown, Antonio, Biesel, Steel and Brown (1995) Nature (London) 374, 62-64]. The myosin VIIA gene is expressed in hair cells in the cochlea, where it is thought to function in the development of the critical neuroepithelium where auditory transduction takes place. In order to understand better the function of myosin VIIA, we have determined the complete sequence of the mouse myosin VIIA cDNA and employed the wild-type sequence for mutational analysis of a number of shaker-1 alleles. Analysis of the mouse myosin VIIA tail sequence demonstrates a large internal repeat with regions of similarity to myosins IV, X and XII as well as members of the band 4.1 family. In addition, the myosin VIIA repeats are similar along their entire length to a tail domain from a plant kinesin. The mouse myosin VIIA tail also contains a putative Src homology 3 (SH3) domain. Along with three previously reported shaker-1 mutations, mutations for seven shaker-1 alleles in total have now been identified. The mutational changes have been analysed in terms of their predicted effect on both myosin motor head and tail domain function and the predictions related to the known phenotypes of the shaker-1 alleles. Five of the mutations lie in the motor head, and analysis of their likely effect on myosin head structure correlates well with the known severity of the shaker-1 alleles. Of the two mutations in the tail, one is a missense mutation within the kinesin and myosin IV, X and XII homology domains that substitutes a conserved amino acid and leads to a severe deafness phenotype. This and other data suggest that myosin VIIA may have properties of a myosin-motor-kinesin-tail hybrid and be involved in membrane turnover within the actin-rich environment of the apical hair cell surface.
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PMID:Mutation analysis of the mouse myosin VIIA deafness gene. 968 Feb 94

The mouse recessive deafness mutation, shaker-2(sh-2), represents a plausible model for an autosomal recessive form of human non-syndromic genetic deafness, DFNB3. Here we report the use of a positional cloning approach to show that the gene mutated in sh-2 mice encodes a novel type of unconventional myosin. A G-to-A transition changing cysteine to tyrosine in the conserved actin binding domain is detected in sh-2 but absent in laboratory strains and wild mice belonging to different mouse subspecies and species. This suggests that the novel myosin gene is a strong candidate for DFNB3.
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PMID:A novel type of myosin encoded by the mouse deafness gene shaker-2. 970 81


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