title: Deficiency of angulin-2/ILDR1, a tricellular tight junction-associated membrane protein, causes deafness with cochlear hair cell degeneration in mice.
abstract: Tricellular tight junctions seal the extracellular spaces of tricellular contacts, where the vertices of three epithelial cells meet, and are required for the establishment of a strong barrier function of the epithelial cellular sheet. Angulins and tricellulin are known as specific protein components of tricellular tight junctions, where angulins recruit tricellulin. Mutations in the genes encoding angulin-2/ILDR1 and tricellulin have been reported to cause human hereditary deafness DFNB42 and DFNB49, respectively. To investigate the pathogenesis of DFNB42, we analyzed mice with a targeted disruption of Ildr1, which encodes angulin-2/ILDR1. Ildr1 null mice exhibited profound deafness. Hair cells in the cochlea of Ildr1 null mice develop normally, but begin to degenerate by two weeks after birth. Tricellulin localization at tricellular contacts of the organ of Corti in the cochlea was retained in Ildr1 null mice, but its distribution along the depth of tricellular contacts was affected. Interestingly, compensatory tricellular contact localization of angulin-1/LSR was observed in the organ of Corti in Ildr1 null mice although it was hardly detected in the organ of Corti in wild-type mice. The onset of hair cell degeneration in Ildr1 null mice was earlier than that in the reported Tric mutant mice, which mimic one of the tricellulin mutations in DFNB49 deafness. These results indicate that the angulin-2/ILDR1 deficiency causes the postnatal degenerative loss of hair cells in the cochlea, leading to human deafness DFNB42. Our data also suggest that angulin family proteins have distinct functions in addition to their common roles of tricellulin recruitment and that the function of angulin-2/ILDR1 for hearing cannot be substituted by angulin-1/LSR.
authors.affiliation: Division of Cell Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Katsuno
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kitajiri
authors.affiliation: Division of Cell Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan; Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Furuse
mesh_terms: D000818:Animals; D003638:Deafness / Q000235:genetics* / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D006198:Hair Cells, Auditory / Q000473:pathology*; D006309:Hearing / Q000235:genetics; D062794:MARVEL Domain Containing 2 Protein / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D009925:Organ of Corti / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D019108:Tight Junctions / Q000235:genetics* / Q000473:pathology
chemical_list: C583885:Ildr1 protein, mouse; D062794:MARVEL Domain Containing 2 Protein; D008565:Membrane Proteins; D011956:Receptors, Cell Surface
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