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EMBO Rep. 2017 Nov;18(11):2015-2029. doi: 10.15252/embr.201643689. Epub 2017 Sep 11.

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing.

Author information

1
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany christian.vogl@med.uni-goettingen.de nstrenzke@med.uni-goettingen.de.
2
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
3
Synaptic Nanophysiology Group, Max-Planck-Institute for Biophysical Chemistry Göttingen, Göttingen, Germany.
4
Institute for Biochemistry I, University Hospital Jena, Jena, Germany.
5
Department for Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH University Medical Center Hamburg Eppendorf, Hamburg, Germany.
6
Department of Physiology, Philipps University Marburg, Marburg, Germany.
7
Department of Immunology and Infectious Diseases, University of Liège CHU Liège, Liège, Belgium.
8
Department of Otorhinolaryngology, University of Liège CHU Liège, Liège, Belgium.
9
Division of Pediatric Hematology and Oncology, Center for Chronic Immunodeficiency and Department of Pediatrics and Adolescent Medicine, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
10
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
11
Institute of Developmental Genetics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
12
Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, München, Germany.
13
German Center for Diabetes Research (DZD), Neuherberg, Germany.
14
Department of Anatomy, University Hospital Jena, Jena, Germany.
15
Institute for Auditory Neuroscience, University Medical Center Göttingen, Göttingen, Germany.
16
Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
17
Auditory Systems Physiology Group Department of Otolaryngology University Medical Center Göttingen, Göttingen, Germany christian.vogl@med.uni-goettingen.de nstrenzke@med.uni-goettingen.de.

Abstract

Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model.

KEYWORDS:

cochlear amplification; hair bundle degeneration; progressive hearing loss; radixin; stereociliar protein transport

PMID:
28893864
PMCID:
PMC5666617
DOI:
10.15252/embr.201643689
[Indexed for MEDLINE]
Free PMC Article

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