title: ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice.
abstract: Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Horta
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;
authors.forename: Clemer
authors.initials: C
authors.lastname: Abad
authors.affiliation: Department of Otolaryngology, Hacettepe University School of Medicine, Ankara, 06100, Turkey;
authors.forename: Levent
authors.initials: L
authors.lastname: Sennaroglu
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;
authors.forename: Joseph
authors.initials: J
authors.lastname: Foster
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146;
authors.forename: Alexandra
authors.initials: A
authors.lastname: DeSmidt
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;
authors.forename: Guney
authors.initials: G
authors.lastname: Bademci
authors.affiliation: Department of Otolaryngology, Hacettepe University School of Medicine, Ankara, 06100, Turkey;
authors.forename: Suna
authors.initials: S
authors.lastname: Tokgoz-Yilmaz
authors.affiliation: Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, 06100, Turkey;
authors.forename: Duygu
authors.identifier: 0000-0001-7583-0349
authors.initials: D
authors.lastname: Duman
authors.affiliation: Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, 06100, Turkey;
authors.forename: F Basak
authors.initials: FB
authors.lastname: Cengiz
authors.affiliation: Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136;
authors.forename: M'hamed
authors.initials: M
authors.lastname: Grati
authors.affiliation: Department of Radiology, Ankara University School of Medicine, Ankara, 06100, Turkey;
authors.forename: Suat
authors.initials: S
authors.lastname: Fitoz
authors.affiliation: Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136;
authors.forename: Xue Z
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136;
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia;
authors.forename: Faiqa
authors.initials: F
authors.lastname: Imtiaz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Currall
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Manchester Academic Health Science Center, University of Manchester, Manchester M13 9NT, United Kingdom;
authors.forename: Cynthia Casson
authors.initials: CC
authors.lastname: Morton
authors.affiliation: Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, 650-0017, Japan;
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
authors.affiliation: Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, 650-0017, Japan;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146;
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136.
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136 mtekin@miami.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D013136:Spiral Ganglion / Q000378:metabolism* / Q000473:pathology; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477011:Ror1 protein, mouse
keywords: NF-κB; deafness; inner ear; innervation; whole-exome sequencing