ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Proc Natl Acad Sci U S A. 2016 May 24;113(21):5993-8. doi: 10.1073/pnas.1522512113.

Oscar Diaz-Horta ¹, Clemer Abad ¹, Levent Sennaroglu ², Joseph Foster 2nd ¹, Alexandra DeSmidt ³, Guney Bademci ¹, Suna Tokgoz-Yilmaz ², Duygu Duman ⁴, F Basak Cengiz ⁴, M'hamed Grati ⁵, Suat Fitoz ⁶, Xue Z Liu ⁵, Amjad Farooq ⁷, Faiqa Imtiaz ⁸, Benjamin B Currall ⁹, Cynthia Casson Morton ¹⁰, Michiru Nishita ¹¹, Yasuhiro Minami ¹¹, Zhongmin Lu ³, Katherina Walz ¹², Mustafa Tekin ¹³

Affiliations

1 John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136;
2 Department of Otolaryngology, Hacettepe University School of Medicine, Ankara, 06100, Turkey;
3 Department of Biology, University of Miami, Miami, FL 33146;
4 Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, 06100, Turkey;
5 Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136;
6 Department of Radiology, Ankara University School of Medicine, Ankara, 06100, Turkey;
7 Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136;
8 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;
9 Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
10 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;
11 Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, 650-0017, Japan;
12 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.
13 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 [email protected].

PMID: 27162350 DOI: 10.1073/pnas.1522512113

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.

Keywords

NF-κB; deafness; inner ear; innervation; whole-exome sequencing.

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