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)

We report here, the localization of a new recessive non-syndromal deafness gene (DFNB12) to 10q21-22 by linkage analysis, of a Sunni family. Affected individuals suffer from congenital profound sensorineural hearing loss. A maximum LOD score of 6.40 (theta = 0.00) was obtained with locus D10S535. Analysis of patients carrying recombinations mapped the gene distal to D10S529 and proximal to D10S532, delineating an interval between 11 and 15 cM. Three deaf mouse mutants Jackson circler (jc), Waltzer (v) and Ames waltzer (av) have been localized to the homologous murine region on chromosome 10. Each of these mouse mutants is a candidate mouse model for the DFNB12-associated hearing impairment.
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PMID:Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22. 881 48

The Ames waltzer (av) mouse mutant is an autosomal recessive deafness mutation on mouse Chromosome 10. Previously, av had not been mapped relative to molecular markers. We have performed an intersubspecific backcross with Mus musculus castaneus and mapped microsatellite markers in this cross. Toothpick PCR on previously frozen tissue samples from offspring was used as an efficient strategy to screen a large number of animals quickly. In 1258 progeny tested we found three recombinants for each of the flanking markers D10Mit199 and D10Mit64. In addition, nine different genes (Ank3, Bcr, Gnaz, Tfam, Mif, Mmp11, Dcoh, Pyp, and Gstt2) were mapped and eliminated genetically as candidate genes for av. av had been discussed as a potential mouse model for the human deafness loci Usher syndrome type ID (USH1D) and DFNB12. Comparative mapping shows that av maps near an evolutionary break point and makes it unlikely that those loci are human homologues of av. A human homologue of av is predicted to lie either on 22q11.2 or on 10q21. The orientation of conserved linkage groups between these two human chromosomal regions relative to mouse Chromosome 10 was determined.
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PMID:Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse chromosome 10. 965 53

Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, approximately 0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.
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PMID:Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. 1109 Mar 41

Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21-q22 and contains the human deafness loci DFNB12 and USH1D). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v(6J), a GT transversion creates a premature stop codon. In v(Alb), a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v(2J), a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v(2J) homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.
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PMID:Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. 1113 8

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.
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PMID:Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. 1113 9

Mutations at the waltzer (v) locus result in deafness and vestibular dysfunction due to degeneration of the neuroepithelium within the inner ear. Here, we use a positional cloning approach to show that waltzer encodes a novel cadherin (Cdh23), which is most closely related to the Drosophila Fat protein. A single nucleotide deletion in the v(J) allele and a single nucleotide insertion in the v allele are predicted to truncate each protein near the N-terminus and produce a functional null allele. In situ hybridization analysis showed that Cdh23 is expressed in the sensory hair cells of the inner ear, where it has been suggested to be a molecule critical for crosslinking of the stereocilia. In addition, Cdh23 is expressed in the urticulo-saccular foramen,the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endolymph. Finally, mutations in human CDH23 have recently been described for two loci, DFNB12 and USH1D, which cause nonsyndromic deafness, identifying waltzer as a mouse model for human hearing loss.
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PMID:Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. 1138 59

Usher syndrome (USH) is defined by the association of sensorineural deafness and visual impairment due to retinitis pigmentosa. The syndrome has three distinct clinical subtypes, referred to as USH1, USH2, and USH3. Each subtype is genetically heterogeneous, and 12 loci have been detected so far. Four genes have been identified, namely, USH1B, USH1C, USH1D, and USH2A. USH1B, USH1C, and USH1D encode an unconventional myosin (myosin VIIA), a PDZ domain-containing protein (harmonin), and a cadherin-like protein (cadherin-23), respectively. Mutations of these genes cause primary defects of the sensory cells in the inner ear, and probably also in the retina. In the inner ear, the USH1 genes, I propose, are involved in the same signaling pathway, which may control development and/or maintenance of the hair bundles of sensory cells via an adhesion force (a) at the junctions between these cells and supporting cells and (b) at the level of the lateral links that interconnect the stereocilia. In contrast, the molecular pathogenesis of USH2A, which is owing to a defect of a novel extracellular matrix protein, is likely to be different from that of USH1.
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PMID:Usher syndrome: from genetics to pathogenesis. 1170 52

Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.
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PMID:CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. 1207 7

Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35-39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G > T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes.
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PMID:Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. 1566 Feb 26

Mutant alleles of the gene encoding cadherin 23 are associated with Usher syndrome type 1 (USH1D), isolated deafness (DFNB12) in humans, and deafness and circling behavior in waltzer (v) mice. Stereocilia of waltzer mice are disorganized and the kinocilia misplaced, indicating the importance of cadherin 23 for hair bundle development. Cadherin 23 was localized to developing stereocilia and proposed as a component of the tip link. We show that, during development of the inner ear, cadherin 23 is initially detected in centrosomes at E14.5, then along the length of emerging stereocilia, and later becomes concentrated at and subsequently disappears from the tops of stereocilia. In mature vestibular hair bundles, cadherin 23 is present along the kinocilium and in the region of stereocilia-kinocilium bonds, a pattern conserved in mammals, chicks, and frogs. Cadherin 23 is also present in Reissner's membrane (RM) throughout development. In homozygous v(6J) mice, a reported null allele, cadherin 23 was absent from stereocilia, but present in kinocilia, RM, and centrosomes. We reconciled these results by identifying two novel isoforms of Cdh23 unaffected in sequence and expression by the v(6J) allele. Our results suggest that Cdh23 participation in stereocilia links may be restricted to developing hair bundles.
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PMID:Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development. 1588 74


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