The BEACH Protein LRBA Is Required for Hair Bundle Maintenance in Cochlear Hair Cells and for Hearing

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

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Animals
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • Evoked Potentials, Auditory, Brain Stem / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Auditory / pathology
  • Hearing / physiology
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / metabolism
  • Hearing Loss, Sensorineural / pathology
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Protein Domains
  • Signal Transduction
  • Sodium-Hydrogen Exchangers / genetics*
  • Sodium-Hydrogen Exchangers / metabolism
  • Spiral Ganglion / metabolism
  • Spiral Ganglion / pathology
  • Stereocilia / metabolism*
  • Stereocilia / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor
  • radixin
  • Lrba protein, mouse