Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011053 (deafness)
 10,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The waltzing guinea pig suffers from hereditary deafness and vestibular disorder. In vestibular organs, hair cells of Type I develop pathologically and will eventually degenerate. They show fusion of sensory hairs, protrusion of the cuticular plate and contain a rod-shaped inclusion body. With fixation techniques designed to preserve proteins it is shown that this rod has a filamentous substructure reminding one of stereocilia. The packing density of the filaments is similar and circular packing patterns are seen within both structures. However, the rod has an irregular cross-section, as opposed to the circular circumference of stereocilia. The filaments in the rod were identified as containing the protein actin (as those in the stereocilia) by decoration with sub-fragment S-1 of myosin. All filaments in the rod have an identical functional polarity, pointing up from the nucleus towards the cuticular plate. This is contrary to that seen in stereocilia, which have filaments pointing down towards the cuticular plate. It is concluded that the rod is not developed by random polymerization of actin but is the result of co-ordinated assembly reminiscent of that which gives rise to stereocilia. The genetic defect appears to be related to mechanisms which determine the site of nucleation and the functional orientation of actin filaments during development.
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PMID:Sensory hairs and filaments rods in vestibular hair cells of the waltzing guinea pig. Organization and identification of actin. 626 95

The shaker-2 mouse with inherited inner ear disease suffers from deafness and a shaking-waltzing behavior. The hair cell type I in cristae ampullares and maculae utriculi show a specific pathology, featuring fusion of the stereocilia and presence of a rod-shaped inclusion body. The inclusion body is composed of filaments that could be identified as the protein actin by the method of decoration with subfragment S-1 of myosin. The functional polarity was determined, and S-1 fragments were found to point apically, that is, from the nucleus up toward the cuticular plate. These observations are identical to those earlier described in the waltzing guinea pig. It is concluded that the identical pathology at a cellular level in two different species may indicate a pathologic disorder in a process fundamental to the normal development of this type of hair cell.
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PMID:Rods of actin filaments in type I hair cells of the Shaker-2 mouse. 688 51

Myosin VIIa is a newly identified member of the myosin superfamily of actin-based motors. Recently, the myosin VIIa gene was identified as the gene defective in shaker-1, a recessive deafness in mice [Gibson, F., Walsh, J., Mburu, P., Varela, A., Brown, K.A., Antonio, M., Beisel, K.W., Steel, K.P. & Brown, S.D.M. (1995) Nature (London) 374, 62-64], and in human Usher syndrome type 1B, an inherited disease characterized by congenital deafness, vestibular dysfunction, and retinitis pigmentosa [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. (1995) Nature (London) 374, 60-61]. To understand the normal function of myosin VIIa and how it could cause these disease phenotypes when defective, we generated antibodies specific to the tail portion of this unconventional myosin. We found that myosin VIIa was expressed in cochlea, retina, testis, lung, and kidney. In cochlea, myosin VIIa expression was restricted to the inner and outer hair cells, where it was found in the apical stereocilia as well as the cytoplasm. In the eye, myosin VIIa was expressed by the retinal pigmented epithelial cells, where it was enriched within the apical actin-rich domain of this cell type. The cell-specific localization of myosin VIIa suggests that the blindness and deafness associated with Usher syndrome is due to lack of proper myosin VIIa function within the cochlear hair cells and the retinal pigmented epithelial cells.
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PMID:Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. 756 24

Usher syndrome represents the association of a hearing impairment with retinitis pigmentosa and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium), nasal ciliar cells and sperm cells, as well as widespread degeneration of the organ of Corti. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH1. USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients. The mouse deafness shaker-1 (sh1) mutation has been localized to the homologous murine region. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1 (ref. 14) led us to consider the human homologue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH1B appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.
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PMID:Defective myosin VIIA gene responsible for Usher syndrome type 1B. 787 Jan 71

Genetic deafness is common, affecting about 1 in 2,000 births. Many of these show primary abnormalities of the sensory neuroepithelia of the inner ear, as do several hearing-impaired mouse mutants, suggesting that genes involved in sensory transduction could be affected. Here we report the identification of one such gene, the mouse shaker-1 (sh1) gene. Shaker-1 homozygotes show hyperactivity, head-tossing and circling due to vestibular dysfunction, together with typical neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti. The sh1 gene encodes an unconventional myosin molecule of the type VII family. Three mutations are described, two mis-sense mutations and a splice acceptor site mutation, all in the region encoding the myosin head. The myosin type VII molecule encoded by sh1 is the first molecule to be identified that is known, by virtue of its mutations, to be involved in auditory transduction.
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PMID:A type VII myosin encoded by the mouse deafness gene shaker-1. 787 Jan 72

The gene encoding human myosin VIIA is responsible for Usher syndrome type III (USH1B), a disease which associates profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. The reconstituted cDNA sequence presented here predicts a 2215 amino acid protein with a typical unconventional myosin structure. This protein is expected to dimerize into a two-headed molecule. The C terminus of its tail shares homology with the membrane-binding domain of the band 4.1 protein superfamily. The gene consists of 48 coding exons. It encodes several alternatively spliced forms. In situ hybridization analysis in human embryos demonstrates that the myosin VIIA gene is expressed in the pigment epithelium and the photoreceptor cells of the retina, thus indicating that both cell types may be involved in the USH1B retinal degenerative process. In addition, the gene is expressed in the human embryonic cochlear and vestibular neuroepithelia. We suggest that deafness and vestibular dysfunction in USH1B patients result from a defect in the morphogenesis of the inner ear sensory cell stereocilia.
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PMID:Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. 862 19

The genetics of deafness is a rapidly expanding area of research. A remarkable total of twenty-two genes involved in non-syndromic deafness in humans have been localized within the past two years, compared with only one known previously. Some of the genes involved in neuroepithelial deafness, the most common type of pathology, have been identified in the past year. Two of these genes encode unconventional myosin molecules. The roles of these and other molecules identified by genetic approaches as important in hearing are being explored.
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PMID:Genetics of deafness. 879 99

Myosin-VIIa is an unconventional myosin with relatively restricted expression. Cloned first from an intestinal epithelium cell line, it occurs most notably in the testis, in the receptor cells of the inner ear, and in the pigment epithelium of the retina. Defects in myosin-VIIa cause the shaker-1 phenotype in mice and Usher syndrome 1B in human, which are characterized by deafness, lack of vestibular function, and (in human) progressive retinal degeneration. Because the described cDNAs encode less than half of the protein predicted from immunoblots, we have cloned cDNAs encoding the rest of human myosin-VIIa. Two transcripts were found, one encoding the predicted 250-kDa protein and another encoding a shorter form. Both transcripts were found in highest abundance in testis, although the shorter transcript was much less abundant. Both could be 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 three other myosins, and a domain similar to the membrane-associated portion of talin and other members of the band-4.1 family.
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PMID:Molecular cloning and domain structure of human myosin-VIIa, the gene product defective in Usher syndrome 1B. 888 67

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.
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PMID:Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. 900 78

Hearing-impaired mouse mutants not only are good models for human hereditary deafness, but also are extremely useful for understanding the molecular basis of the cochlear defect. We describe here how we identified the gene responsible for the deafness and vestibular defects in the shaker-1 mouse mutant as a myosin VII gene. Three different mutations, all causing the same phenotype in different lines of mouse, were found, providing good evidence that we had, indeed, found the correct gene. The same gene was subsequently found to be involved in Usher's syndrome type 1B, which features deafness, vestibular dysfunction, and progressive retinitis pigmentosa. The myosin VII gene is expressed in sensory hair cells, but not in supporting cells or neurons. We are investigating the role of myosin VII in hair cell development and function. Analysis of the different mutant stocks suggests it has at least two functions. First it is involved in the development and maintenance of the stereocilia bundle. Second, it has a role in inner hair cell function. No evidence of retinal degeneration like that in Usher's syndrome has been found in the shaker-1 mutants so far studied. The benefits of understanding the function of the gene for families with Usher's type 1B are discussed. This gene is the first to be identified as causing the most common type of disorder in human hearing impairment, neuroepithelial abnormalities, and suggests a new class of candidate genes for involvement in such defects.
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PMID:Unravelling the genetics of deafness. 915 19


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