TY - JOUR
T1 - A study of whirlin isoforms in the mouse vestibular system suggests potential vestibular dysfunction in DFNB31-deficient patients
AU - Mathur, Pranav Dinesh
AU - Vijayakumar, Sarath
AU - Vashist, Deepti
AU - Jones, Sherri M.
AU - Jones, Timothy A.
AU - Yang, Jun
PY - 2015
Y1 - 2015
N2 - 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 (Dfnb31wi/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 Dfnb31wi/wi vestibular organs, while only C-whirlin is expressed in Dfnb31neo/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 Dfnb31neo/neo and Dfnb31wi/wi mice. Swimming and rotarod tests demonstrate that the two Dfnb31 mutants have balance problems, with Dfnb31wi/wi mice being more affected than Dfnb31neo/neo mice. Because Dfnb31wi/wi and Dfnb31neo/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.
AB - 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 (Dfnb31wi/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 Dfnb31wi/wi vestibular organs, while only C-whirlin is expressed in Dfnb31neo/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 Dfnb31neo/neo and Dfnb31wi/wi mice. Swimming and rotarod tests demonstrate that the two Dfnb31 mutants have balance problems, with Dfnb31wi/wi mice being more affected than Dfnb31neo/neo mice. Because Dfnb31wi/wi and Dfnb31neo/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.
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U2 - 10.1093/hmg/ddv403
DO - 10.1093/hmg/ddv403
M3 - Article
C2 - 26420843
AN - SCOPUS:84959236550
VL - 24
SP - 7017
EP - 7030
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 24
ER -