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The mechanosensory structure of the hair cell requires clarin-1, a protein encoded by Usher syndrome III causative gene.

Mutation in the clarin-1 gene (Clrn1) results in loss of hearing and vision in humans (Usher syndrome III), but the role of clarin-1 in the sensory hair cells is unknown. Clarin-1 is predicted to be a four transmembrane domain protein similar to members of the tetraspanin family. Mice carrying null mutation in the clarin-1 gene (Clrn1(-/-)) show loss of hair cell function and a possible defect in ribbon synapse. We investigated the role of clarin-1 using various in vitro and in vivo approaches. We show by immunohistochemistry and patch-clamp recordings of Ca(2+) currents and membrane capacitance from inner hair cells that clarin-1 is not essential for formation or function of ribbon synapse. However, reduced cochlear microphonic potentials, FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] loading, and transduction currents pointed to diminished cochlear hair bundle function in Clrn1(-/-) mice. Electron microscopy of cochlear hair cells revealed loss of some tall stereocilia and gaps in the v-shaped bundle, although tip links and staircase arrangement of stereocilia were not primarily affected by Clrn1(-/-) mutation. Human clarin-1 protein expressed in transfected mouse cochlear hair cells localized to the bundle; however, the pathogenic variant p.N48K failed to localize to the bundle. The mouse model generated to study the in vivo consequence of p.N48K in clarin-1 (Clrn1(N48K)) supports our in vitro and Clrn1(-/-) mouse data and the conclusion that CLRN1 is an essential hair bundle protein. Furthermore, the ear phenotype in the Clrn1(N48K) mouse suggests that it is a valuable model for ear disease in CLRN1(N48K), the most prevalent Usher syndrome III mutation in North America.

Pubmed ID: 22787034

Authors

  • Geng R
  • Melki S
  • Chen DH
  • Tian G
  • Furness DN
  • Oshima-Takago T
  • Neef J
  • Moser T
  • Askew C
  • Horwitz G
  • Holt JR
  • Imanishi Y
  • Alagramam KN

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

July 11, 2012

Associated Grants

  • Agency: NIDCD NIH HHS, Id: R01 DC005439
  • Agency: NIDCD NIH HHS, Id: R01 DC010816
  • Agency: NIDCD NIH HHS, Id: R01-DC010816
  • Agency: NIDCD NIH HHS, Id: R01-DC05439

Mesh Terms

  • Acoustic Stimulation
  • Age Factors
  • Alcohol Oxidoreductases
  • Animals
  • Animals, Newborn
  • Asparagine
  • Barium
  • Biophysical Processes
  • Cadherins
  • Cell Line, Transformed
  • Cochlea
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Evoked Potentials, Auditory, Brain Stem
  • Green Fluorescent Proteins
  • Hair Cells, Auditory
  • Humans
  • Lysine
  • Mechanoreceptors
  • Membrane Potentials
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Mutation
  • Nerve Fibers
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Physical Stimulation
  • Psychoacoustics
  • Pyridinium Compounds
  • Quaternary Ammonium Compounds
  • Receptors, AMPA
  • Synapses
  • Transfection
  • Usher Syndromes