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FLASH GENE

Symbol

PCDH15

contributors: mct/shn - updated : 12-12-2017

HGNC name	protocadherin-related 15
HGNC id	14674

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Homo sapiens Hearing/Equilibrium ear inner cochlea   highly Homo sapiens Nervous brain hindbrain cerebellum   moderately Homo sapiens   brain       moderately Homo sapiens Reproductive female system breast     lowly Homo sapiens Urinary kidney       moderately Homo sapiens Visual eye retina     highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Hearing / Equilibrium hair cell receptor Homo sapiens Visual cone photoreceptor Homo sapiens Visual rod 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 other’s 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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