title: Downsloping high-frequency hearing loss due to inner ear tricellular tight junction disruption by a novel ILDR1 mutation in the Ig-like domain.
abstract: The immunoglobulin (Ig)-like domain containing receptor 1 (ILDR1) gene encodes angulin-2/ILDR1, a recently discovered tight junction protein, which forms tricellular tight junction (tTJ) structures with tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) at tricellular contacts (TCs) in the inner ear. Previously reported recessive mutations within ILDR1 have been shown to cause severe to profound nonsyndromic sensorineural hearing loss (SNHL), DFNB42. Whole-exome sequencing of a Korean multiplex family segregating partial deafness identified a novel homozygous ILDR1 variant (p.P69H) within the Ig-like domain. To address the pathogenicity of p.P69H, the angulin-2/ILDR1 p.P69H variant protein, along with the previously reported pathogenic ILDR1 mutations, was expressed in angulin-1/LSR knockdown epithelial cells. Interestingly, partial mislocalization of the p.P69H variant protein and tricellulin at TCs was observed, in contrast to a severe mislocalization and complete failure of tricellulin recruitment of the other reported ILDR1 mutations. Additionally, three-dimensional protein modeling revealed that angulin-2/ILDR1 contributed to tTJ by forming a homo-trimer structure through its Ig-like domain, and the p.P69H variant was predicted to disturb homo-trimer formation. In this study, we propose a possible role of angulin-2/ILDR1 in tTJ formation in the inner ear and a wider audiologic phenotypic spectrum of DFNB42 caused by mutations within ILDR1.
authors: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
authors: Nayoung K D
authors: NK
authors: Kim
authors: Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tomohito
authors: T
authors: Higashi
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors: Kyoung Yeul
authors: KY
authors: Lee
authors: Otorhinolaryngology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Korea.
authors: Ah Reum
authors: AR
authors: Kim
authors: Department of Otolaryngology- Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Shin-ichiro
authors: S
authors: Kitajiri
authors: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Min Young
authors: MY
authors: Kim
authors: Otorhinolaryngology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Korea.
authors: Mun Young
authors: MY
authors: Chang
authors: Department of Cell and Systems Biology, University of Toronto St. George, Toronto, Canada.
authors: Veronica
authors: V
authors: Kim
authors: Otorhinolaryngology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Korea.
authors: Seung-Ha
authors: SH
authors: Oh
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors: Dongsup
authors: D
authors: Kim
authors: Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Mikio
authors: M
authors: Furuse
authors: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors: Woong-Yang
authors: WY
authors: Park
authors: Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Byung Yoon
authors: BY
authors: Choi
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D044466:Asian People; D007758:Ear, Inner / Q000378:metabolism* / Q000473:pathology; D006316:Hearing Loss, High-Frequency / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D055503:Protein Multimerization / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism*
chemical_list: C493788:ILDR1 protein, human; D011956:Receptors, Cell Surface