Researchers from King's College London and the Wellcome Trust
Sanger Institute have for the first time demonstrated a direct link
between the Wbp2 gene and progressive hearing loss.
The scientists found that loss of Wbp2 expression led to
progressive high-frequency hearing loss in mice as well as in two
clinical cases of children with deafness with no other obvious
features. This study opens up the Wbp2 pathway as a new route to
therapeutic approaches that more specifically target the inner
ear.
These findings also indicate that hearing impairment is linked
to hormonal signalling, rather than hair cell degeneration. Wbp2 is
known to be a transcriptional co-activator for estrogen receptor
Esr1 and progesterone receptor Pgr. The loss of Wbp2 causes not
only progressive high frequency hearing loss, but also results in
reduced expression of Esr1, Esr2 and Pgr in the cochlea - a part of
the inner ear.
Understanding the estrogen-sensitive molecular networks specific
to hearing offers an unprecedented new target for the control of
the estrogen signalling pathway in the auditory system that could
prevent or reverse progressive hearing loss.
Professor Karen Steel of King's College London said: "Our study
demonstrates that hearing thresholds are normal in young Wbp2
mutant mice, but are raised at high frequencies by four weeks of
age.
"More importantly, we also demonstrate that Wbp2 is crucial for
hearing in humans. We found two children affected by severe to
profound deafness, each carrying two variants of the Wbp2
gene."
Progressive hearing loss is very common, yet little is known
about its molecular mechanisms. As a result, targets for medical
therapies have been lacking. It has been known that estrogen
signalling protects against noise-induced hearing loss. However,
estrogen-based therapies have not been generally considered for
hearing impairment due to their widespread effects.
Wbp2 was found to be involved in progressive hearing loss during
a large-scale screen for hearing defects in newly-generated
targeted mouse mutants. The finding of a new gene involved in human
deafness following the initial discovery of its role in the mouse
also emphasises the value of mouse genetics research for better
understanding human disease.
The paper, Wbp2 is required for normal glutamatergic synapses in the cochlea
and is crucial for hearing, is published in EMBO Molecular
Medicine.