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A study of whirlin isoforms in the mouse vestibular system suggests potential vestibular dysfunction in DFNB31-deficient patients.

Abstract
The DFNB31 gene plays an indispensable role in the cochlea and retina. Mutations in this gene disrupt its various isoforms and lead to non-syndromic deafness, blindness and deaf-blindness. However, the known expression of Dfnb31, the mouse ortholog of DFNB31, in vestibular organs and the potential vestibular-deficient phenotype observed in one Dfnb31 mutant mouse (Dfnb31(wi/wi)) suggest that DFNB31 may also be important for vestibular function. In this study, we find that full-length (FL-) and C-terminal (C-) whirlin isoforms are expressed in the vestibular organs, where their stereociliary localizations are similar to those of developing cochlear inner hair cells. No whirlin is detected in Dfnb31(wi/wi) vestibular organs, while only C-whirlin is expressed in Dfnb31(neo/neo) vestibular organs. Both FL- and C-whirlin isoforms are required for normal vestibular stereociliary growth, although they may play slightly different roles in the central and peripheral zones of the crista ampullaris. Vestibular sensory-evoked potentials demonstrate severe to profound vestibular deficits in Dfnb31(neo/neo) and Dfnb31(wi/wi) mice. Swimming and rotarod tests demonstrate that the two Dfnb31 mutants have balance problems, with Dfnb31(wi/wi) mice being more affected than Dfnb31(neo/neo) mice. Because Dfnb31(wi/wi) and Dfnb31(neo/neo) mice faithfully recapitulate hearing and vision symptoms in patients, our findings of vestibular dysfunction in these Dfnb31 mutants raise the question of whether DFNB31-deficient patients may acquire vestibular as well as hearing and vision loss.
AuthorsPranav Dinesh Mathur, Sarath Vijayakumar, Deepti Vashist, Sherri M Jones, Timothy A Jones, Jun Yang
JournalHuman molecular genetics (Hum Mol Genet) Vol. 24 Issue 24 Pg. 7017-30 (Dec 15 2015) ISSN: 1460-2083 [Electronic] England
PMID26420843 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
Chemical References
  • Membrane Proteins
  • Protein Isoforms
  • WHRN protein, human
  • Whrn protein, mouse
Topics
  • Animals
  • Disease Models, Animal
  • Ear, Inner (pathology, physiopathology)
  • Hair Cells, Auditory (pathology)
  • Hearing Loss, Sensorineural (genetics, physiopathology)
  • Humans
  • Membrane Proteins (deficiency, genetics)
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Postural Balance
  • Protein Isoforms (genetics)

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