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FLASH GENE
Symbol PCDH15 contributors: mct/shn - updated : 12-12-2017
HGNC name protocadherin-related 15
HGNC id 14674
Corresponding disease
DFNB23 neurosensory deafness 23
USH1F Usher syndrome type 1F
Location 10q21.1      Physical location : 55.562.534 - 56.561.051
Synonym name
  • protocadherin 15
  • cadherin-related family member 15
  • deafness, autosomal recessive 23
  • Synonym symbol(s) RP11-449J3.2, CDHR15, DFNB23, DKFZp667A1711, USH1F
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head, gene in gene
    text CAMKG, NDST2, PLAU are nested in the introns of PCDH15
    STRUCTURE 998.52 kb     35 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    text structure
  • promoter lacks TATAA or CAAT sequences within 100 bases upstream of the transcription start site
  • a CpG island 215 bp long was found approximately 2.9 kb upstream of the transcriptional start site
  • MAPPING cloned Y linked Y status provisional
    Map cen - D10S1762 - D10S1643 - PCDH15 - D10S1226 - D10S596 - ter
    Physical map
    LOC387678 10 similar to ARF GTPase-activating protein LOC389965 10 similar to Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3) (NHE-3) LOC387679 10 similar to KIAA0592 protein LOC387680 10 similar to KIAA0592 protein LOC389966 10 similar to Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3) (NHE-3) ASAH2 10q11.21 N-acylsphingosine amidohydrolase (non-lysosomal ceramidase) 2 LOC387681 10 hypothetical gene supported by BT007130; NM_001378 MOB 10q11.2 mob protein LOC340858 10q21.1 similar to hypothetical protein FLJ10539 FLJ31958 10q21.1 hypothetical protein FLJ31958 LOC389967 10 similar to bA182L21.1 (novel protein similar to hypothetical proteins) LOC389968 10 similar to Cathepsin L preproprotein LOC283023 10q21.1 similar to Geranylgeranyl transferase type I beta subunit (Type I protein geranyl-geranyltransferase beta subunit) (GGTase-I-beta) ACF 10q21,1 similar to Geranylgeranyl transferase type I beta subunit (Type I protein geranyl-geranyltransferase beta subunit) (GGTase-I-beta) PRKG1 10q11.2 protein kinase, cGMP-dependent, type I CSTF2T 10q22-q23 protein kinase, cGMP-dependent, type I DKK1 10q11.2 dickkopf homolog 1 (Xenopus laevis) LOC389969 10 similar to ribosomal protein L31 LOC387682 10 similar to 52 kDa repressor of the inhibitor of the protein kinase (p58IPK-interacting protein) (58 kDa interferon-induced protein kinase-interacting protein) (P52rIPK) (Death associated protein 4) (THAP domain protein 0) MBL2 10q11.2-q21 mannose-binding lectin (protein C) 2, soluble (opsonic defect) LOC387683 10 LOC387683 PCDH15 10q21.1 protocadherin 15 LOC389970 10 similar to Glyceraldehyde 3-phosphate dehydrogenase, liver (GAPDH) ZWINT 10q21-q22 ZW10 interactor
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    35 splicing 5803 - 1539 - 2014 2494000
  • CD2-2, transcript variant J
  • essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization
  • 36 splicing 5768 - 1790 - 2014 2494000
  • CD2-1, transcript variant I
  • essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization
  • 35 splicing 9237 - 1677 - 2014 2494000
    CD3-2, transcript variant L
    35 splicing 9252 - 1682 - 2014 2494000
  • CD3-1, transcript variant K
  • 32 splicing 7042 180 1962 inner ear hair cell stereocilia and retinal outer photoreceptor segments 2014 2494000
  • isoform CD1-1, transcript variant A
  • corresponds to the full-length molecule
  • 35 splicing 7027 - 1957 - 2014 2494000
  • CD1-2
  • transcript variant B
  • 34 splicing 6814 - 1886 - 2014 2494000
  • CD1-6, transcript variant D
  • 35 splicing 7012 - 1952 - 2014 2494000
  • CD1-7, transcript variant E
  • 34 splicing 6901 - 1915 - 2014 2494000
  • CD1-8, transcript variant F
  • 34 splicing 6961 - 1935 - 2014 2494000
  • CD1-9, transcript variant G
  • 34 splicing 6952 - 1932 - 2014 2494000
  • CD1-10, transcript variant H
  • 35 splicing 7021 - 1955 - 2014 2494000
  • CD1-4, transcript variant C
  • - - 6922 - 1933 - 2014 2494000
  • CD1-a
  • - - 5917 - 1783 - 2014 2494000
  • CD2-a
  • is an essential component of tip-links in mature auditory hair cells
  • - - 9245 - 1675 - 2014 2494000
  • CD3-a
  • EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately Homo sapiens
    Hearing/Equilibriumearinnercochlea highly Homo sapiens
    Nervousbrainhindbraincerebellum moderately Homo sapiens
     brain   moderately Homo sapiens
    Reproductivefemale systembreast  lowly Homo sapiens
    Urinarykidney   moderately Homo sapiens
    Visualeyeretina  highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Hearing / Equilibriumhair cell receptor Homo sapiens
    Visualcone photoreceptor Homo sapiens
    Visualrod photoreceptor Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminus contains polar amino acids (Elledge 2010)
  • a signal peptide
  • 11 extracellular cadherin (EC) repeats, with canonical EC4-5 linker binding three Ca2+ ions, and non-canonical EC3-4 linker binding only two Ca2+ ions
  • a transmembrane segment encoded by a large unique exon
  • a cytoplasmic domain containing two proline-rich regions
  • a polyadenylation signal
  • conjugated GlycoP
    isoforms Precursor
    HOMOLOGY
    interspecies ortholog to Pcdh15, Mus musculus
    ortholog to Pcdh15, Rattus norvegicus
    ortholog to PCDH15, Pan troglodytes
    intraspecies homolog to cadherin
    homolog to PCDH23
    homolog to CDH23
    Homologene
    FAMILY
  • cadherin superfamily of calcium dependent cell-cell adhesion glycoproteins
  • protocadherin subfamily
  • CATEGORY adhesion , receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane,junction
        intracellular
    intracellular,nuclear envelope,int
    text
  • integral plasma membrane,localized at the synaptic junction
  • expressed in photoreceptor cells of the mammalian retina, where it is colocalized with harmonin, myosin VIIa, and cadherin 23 at the synaptic terminal
  • basic FUNCTION
  • maintaining normal function of inner ear and retina
  • mediating adhesion in synaptic junctions through lack-in process
  • playing an essential role in maintaining the normal organization of the stereocilia bundle
  • CDH23, PCDH15 and ADGRV1 have been implicated in the development of cochlear hair cell stereocilia, while CLRN1 has been suggested to also play a role in synaptogenesis
  • USH1G, MYO7A, USH1C, CDH23, PCDH15 form an adhesion belt around the basolateral region of the photoreceptor outer segment, and defects in this structure cause the retinal degeneration in USH1 patients
  • PCDH15 and LHFPL5 facilitate each otherís cell surface transport
  • is a central component of the mechanotransduction complex in auditory and vestibular hair cells
  • is a core component of hair cell tip-links and crucial for proper function of inner ear hair cells
  • CELLULAR PROCESS cell organization/biogenesis
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling signal transduction , sensory transduction/hearing
    cell-cell signaling
    a component
  • TMIE forms a ternary complex with the tip-link component PCDH15 and its binding partner LHFPL5
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Ca2+
  • protein
  • interacted with harmonin USH1C (probably play a role in disk morphogenesis)
  • interact CDH23 to form a filament with structural similarity to tip links, in sensory hair cells
  • CDH23 and PCDH15 interact to form tip links, which gate mechanotransduction channels in hair cells of the inner ear (Elledge 2010)
  • cytoplasmic N-terminus of HCN1 binds the cytoplasmic C-terminus of stereociliary tip-link protein PCDH15
  • is an integral component of the hair cells mechanotransduction machinery that functionally couples PCDH15 to the transduction channel
  • CDH23, PCDH15 bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats ofCDH23, PCDH15
  • PCDH15 interacts with transmembrane channel-like proteins TMC1 and TMC2
  • both LHFPL5 and TMC1 were shown to interact with PCDH15, a component of the tip link, which applies force to the mechanotransducer (MT) channel
  • interaction of MYO3A with the cytosolic tail of the integral tip-link protein protocadherin 15 (PCDH15), a core component of MET complex
  • GOPC, a Golgi-associated, PDZ domain-containing protein, interacts with PCDH15
  • CDH23 and PCDH15, interact in a Ca2+-dependent manner to form tip links
  • cell & other
  • cell cell homophilic interaction
  • REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) USH1F , DFNB23
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in cytotoxic tumor-derived T- and NK-cell lines as well as in biopsies of nasal NK/T-cell lymphomas
    Susceptibility
  • to familial combined hyperlipidemia
  • to Noise-induced hearing loss (NIHL)
  • Variant & Polymorphism SNP
  • nonsynonymous SNP within PCDH15 is associated with lipid traits in familial combined hyperlipidemia (Huertas-Vazquez 2010)
  • genetic variations in PCDH15 modify the susceptibility to NIHL development
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Ames waltzer a recessive mutation in mice causes deafness and a balance disorder associated with the degeneration of inner ear neuroepithelia
  • Digenic heterozygotes mice for cadherin 23 and protocadherin 15 display a significant levels of hearing loss, cytoarchitectural defects in the cochlea, degeneration of the stereocilia and a base-apex loss of hair cells and spiral ganglion cells
  • Pcdh15-CD2-deficient mice are deaf, lack kinociliary links and have abnormally polarized hair bundles
  • noddy homozygotes lack inner ear function, and noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of Pcdh15