Cadherins form a large family of proteins often involved in calcium-dependent cellular adhesion. Although classical members of the family can provide a physical bond between cells, a subset of special cadherins use their extracellular domains to interlink apical specializations of single epithelial sensory cells. Two of these cadherins, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), form extracellular "tip link" filaments that connect apical bundles of stereocilia on hair cells essential for inner-ear mechanotransduction. As these bundles deflect in response to mechanical stimuli from sound or head movements, tip links gate hair-cell mechanosensitive channels to initiate sensory perception. Here, we review the unusual and diverse structural properties of these tip-link cadherins and the functional significance of their deafness-related missense mutations. Based on the structural features of CDH23 and PCDH15, we discuss the elasticity of tip links and models that bridge the gap between the nanomechanics of cadherins and the micromechanics of hair-cell bundles during inner-ear mechanotransduction.
Sensitivity, polarity, and conductance change in the response of vertebrate hair cells to controlled mechanical stimuli
Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell
A monoclonal antibody disrupting calcium-dependent cell-cell adhesion of brain tissues: possible role of its target antigen in animal pattern formation
Cross-links between stereocilia in the guinea pig organ of Corti, and their possible relation to sensory transduction
Directional sensitivity of individual vertebrate hair cells to controlled deflection of their hair bundles
Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23
The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene
Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D
CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle
Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family
PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23
Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle
Duplicated genes with split functions: independent roles of protocadherin15 orthologues in zebrafish hearing and vision
Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia
Cadherin 23 is a component of the transient lateral links in the developing hair bundles of cochlear sensory cells
Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development
Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%
The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles
The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15
Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning
Distribution and frequencies of CDH23 mutations in Japanese patients with non-syndromic hearing loss
The dimensions and structural attachments of tip links in mammalian cochlear hair cells and the effects of exposure to different levels of extracellular calcium
UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes
MAGI-1, a candidate stereociliary scaffolding protein, associates with the tip-link component cadherin 23
A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells
Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23
Molecular screening of deafness in Algeria: high genetic heterogeneity involving DFNB1 and the Usher loci, DFNB2/USH1B, DFNB12/USH1D and DFNB23/USH1F
Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families
Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members
Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids
A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs
Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15
Asymmetric distribution of cadherin 23 and protocadherin 15 in the kinocilial links of avian sensory hair cells
Nanomechanics of the cadherin ectodomain: "canalization" by Ca2+ binding results in a new mechanical element.
Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain
Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells
An ENU-induced mutation of Cdh23 causes congenital hearing loss, but no vestibular dysfunction, in mice
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families
Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes
Crystal structures of Drosophila N-cadherin ectodomain regions reveal a widely used class of Ca²+-free interdomain linkers
Usher syndrome (sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches
Stereocilia membrane deformation: implications for the gating spring and mechanotransduction channel
Molecular diagnostics for congenital hearing loss including 15 deafness genes using a next generation sequencing platform
Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia
Prevalence and clinical features of hearing loss patients with CDH23 mutations: a large cohort study
Evolution of sound and balance perception: innovations that aggregate single hair cells into the ear and transform a gravistatic sensor into the organ of corti
Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice
Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells
The composition and role of cross links in mechanoelectrical transduction in vertebrate sensory hair cells
TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear
Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients
Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE
The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells
Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells
Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next generation sequencing approaches
Unconventional mechanics of lipid membranes: a potential role for mechanotransduction of hair cell stereocilia
TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia
Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss
Rod disc renewal occurs by evagination of the ciliary plasma membrane that makes cadherin-based contacts with the inner segment
Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer
Detection and Confirmation of Deafness-Causing Copy Number Variations in the STRC Gene by Massively Parallel Sequencing and Comparative Genomic Hybridization
Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
Mechanotransduction current is essential for stability of the transducing stereocilia in mammalian auditory hair cells
The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells
Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt).
Chemomechanical regulation of myosin Ic cross-bridges: Deducing the elastic properties of an ensemble from single-molecule mechanisms
Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases
The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex.
Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception
Comparative transcriptome analysis of auditory OC-1 cells and zebrafish inner ear tissues in the absence of human OSBPL2 orthologues
Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia.
Crystal structure of the nonclassical cadherin-17 N-terminus and implications for its adhesive binding mechanism.
Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases
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