Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
WHRN (DFNB31) mutations cause diverse hearing disorders: profound deafness (DFNB31) or variable hearing loss in Usher syndrome type II. The known role of WHRN in stereocilia elongation does not explain these different pathophysiologies. Using spontaneous and targeted Whrn mutants, we show that the major long (WHRN-L) and short (WHRN-S) isoforms of WHRN have distinct localizations within stereocilia and also across hair cell types. Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction. WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction. WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation. WHRN-L localizes midway along the shorter stereocilia, at the level of inter-stereociliary links. We propose that differential isoform expression underlies the variable auditory and vestibular phenotypes associated with WHRN mutations.
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.
Seham
S
Ebrahim
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Neil J
NJ
Ingham
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.
Morag A
MA
Lewis
MRC Institute of Hearing Research, Nottingham NG7 2RD, UK.
Michael J C
MJC
Rogers
National Institute on Deafness and Other Communications Disorders, NIH, Bethesda, MD 20892, USA.
Runjia
R
Cui
National Institute on Deafness and Other Communications Disorders, NIH, Bethesda, MD 20892, USA.
Bechara
B
Kachar
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Johanna C
JC
Pass
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; MRC Institute of Hearing Research, Nottingham NG7 2RD, UK. Electronic address: karen.steel@kcl.ac.uk.
Karen P
KP
Steel
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D055724:Electrophysiological Phenomena; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000648:ultrastructure; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D059547:Stereocilia / Q000378:metabolism* / Q000648:ultrastructure; D014722:Vestibule, Labyrinth / Q000502:physiology
D008565:Membrane Proteins; D020033:Protein Isoforms; C477218:Whrn protein, mouse