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

TY - JOUR

T1 - The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

AU - Vogl, Christian

AU - Butola, Tanvi

AU - Haag, Natja

AU - Hausrat, Torben J

AU - Leitner, Michael G

AU - Moutschen, Michel

AU - Lefèbvre, Philippe P

AU - Speckmann, Carsten

AU - Garrett, Lillian

AU - Becker, Lore

AU - Fuchs, Helmut

AU - Hrabe de Angelis, Martin

AU - Nietzsche, Sandor

AU - Kessels, Michael M

AU - Oliver, Dominik

AU - Kneussel, Matthias

AU - Kilimann, Manfred W

AU - Strenzke, Nicola

N1 - © 2017 The Authors.

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.15252/embr.201643689

DO - 10.15252/embr.201643689

M3 - SCORING: Journal article

C2 - 28893864

VL - 18

SP - 2015

EP - 2029

JO - EMBO REP

JF - EMBO REP

SN - 1469-221X

IS - 11

ER -