Tricellulin is a tight-junction protein necessary for hearing.
The inner ear has fluid-filled compartments of different ionic compositions, including the endolymphatic and perilymphatic spaces of the organ of Corti; the separation from one another by epithelial barriers is required for normal hearing. TRIC encodes tricellulin, a recently discovered tight-junction (TJ) protein that contributes to the structure and function of tricellular contacts of neighboring cells in many epithelial tissues. We show that, in humans, four different recessive mutations of TRIC cause nonsyndromic deafness (DFNB49), a surprisingly limited phenotype, given the widespread tissue distribution of tricellulin in epithelial cells. In the inner ear, tricellulin is concentrated at the tricellular TJs in cochlear and vestibular epithelia, including the structurally complex and extensive junctions between supporting and hair cells. We also demonstrate that there are multiple alternatively spliced isoforms of TRIC in various tissues and that mutations of TRIC associated with hearing loss remove all or most of a conserved region in the cytosolic domain that binds to the cytosolic scaffolding protein ZO-1. A wild-type isoform of tricellulin, which lacks this conserved region, is unaffected by the mutant alleles and is hypothesized to be sufficient for structural and functional integrity of epithelial barriers outside the inner ear.
Riazuddin
Saima
S
Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
Ahmed
Zubair M
ZM
Fanning
Alan S
AS
Lagziel
Ayala
A
Kitajiri
Shin-ichiro
S
Ramzan
Khushnooda
K
Khan
Shaheen N
SN
Chattaraj
Parna
P
Friedman
Penelope L
PL
Anderson
James M
JM
Belyantseva
Inna A
IA
Forge
Andrew
A
Riazuddin
Sheikh
S
Friedman
Thomas B
TB
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D007758:Ear, Inner / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006309:Hearing / Q000235:genetics*; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D062794:MARVEL Domain Containing 2 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D062793:Occludin; D009925:Organ of Corti / Q000378:metabolism; D010375:Pedigree; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D062826:Zonula Occludens-1 Protein
D062794:MARVEL Domain Containing 2 Protein; C516798:MARVELD2 protein, human; C508309:Marveld2 protein, mouse; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D020033:Protein Isoforms; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein