A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice.

The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/2005; 102(22):7894-9. DOI: 10.1073/pnas.0500760102
Source: PubMed

ABSTRACT Mouse deafness mutations provide valuable models of human hearing disorders and entry points into molecular pathways important to the hearing process. A newly discovered mouse mutation named hurry-scurry (hscy) causes deafness and vestibular dysfunction. Scanning electron microscopy of cochleae from 8-day-old mutants revealed disorganized hair bundles, and by 50 days of age, many hair cells are missing. To positionally clone hscy, 1,160 F(2) mice were produced from an intercross of (C57BL/6-hscy x CAST/EiJ) F(1) hybrids, and the mutation was localized to a 182-kb region of chromosome 17. A missense mutation causing a critical cysteine to phenylalanine codon change was discovered in a previously undescribed gene within this candidate interval. The gene is predicted to encode an integral membrane protein with four transmembrane helices. A synthetic peptide designed from the predicted protein was used to produce specific polyclonal antibodies, and strong immunoreactivity was observed on hair bundles of both inner and outer hair cells in cochleae of newborn +/+ controls and +/hscy heterozygotes but was absent in hscy/hscy mutants. Accordingly, the gene was given the name "tetraspan membrane protein of hair cell stereocilia," symbol Tmhs. Two related proteins (>60% amino acid identity) are encoded by genes on mouse chromosomes 5 and 6 and, together with the Tmhs-encoded protein (TMHS), comprise a distinct tetraspan subfamily. Our localization of TMHS to the apical membrane of inner ear hair cells during the period of stereocilia formation suggests a function in hair bundle morphogenesis.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Identification of the auditory hair cell mechano-electrical transduction (hcMET) channel has been a major focus in the hearing research field since the 1980s when direct mechanical gating of a transduction channel was proposed (Corey and Hudspeth J Neurosci 3:962-976, 1983). To this day, the molecular identity of this channel remains controversial. However, many of the hcMET channel's properties have been characterized, including pore properties, calcium-dependent ion permeability, rectification, and single channel conductance. At this point, elucidating the molecular identity of the hcMET channel will provide new tools for understanding the mechanotransduction process. This review discusses the significance of identifying the hcMET channel, the difficulties associated with that task, as well as the establishment of clear criteria for this identification. Finally, we discuss potential candidate channels in light of these criteria.
    Pflügers Archiv - European Journal of Physiology 09/2014; DOI:10.1007/s00424-014-1606-z · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Much is known about the mechanotransducer (MT) channels mediating transduction in hair cells of the vertrbrate inner ear. With the use of isolated preparations, it is experimentally feasible to deliver precise mechanical stimuli to individual cells and record the ensuing transducer currents. This approach has shown that small (1-100 nm) deflections of the hair-cell stereociliary bundle are transmitted via interciliary tip links to open MT channels at the tops of the stereocilia. These channels are cation-permeable with a high selectivity for Ca(2+); two channels are thought to be localized at the lower end of the tip link, each with a large single-channel conductance that increases from the low- to high-frequency end of the cochlea. Ca(2+) influx through open channels regulates their resting open probability, which may contribute to setting the hair cell resting potential in vivo. Ca(2+) also controls transducer fast adaptation and force generation by the hair bundle, the two coupled processes increasing in speed from cochlear apex to base. The molecular intricacy of the stereocilary bundle and the transduction apparatus is reflected by the large number of single-gene mutations that are linked to sensorineural deafness, especially those in Usher syndrome. Studies of such mutants have led to the discovery of many of the molecules of the transduction complex, including the tip link and its attachments to the stereociliary core. However, the MT channel protein is still not firmly identified, nor is it known whether the channel is activated by force delivered through accessory proteins or by deformation of the lipid bilayer.
    Physiological Reviews 07/2014; 94(3):951-986. DOI:10.1152/physrev.00038.2013 · 29.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Uniquely among human senses, hearing is not simply a passive response to stimulation. Our auditory system is instead enhanced by an active process in cochlear hair cells that amplifies acoustic signals several hundred-fold, sharpens frequency selectivity and broadens the ear's dynamic range. Active motility of the mechanoreceptive hair bundles underlies the active process in amphibians and some reptiles; in mammals, this mechanism operates in conjunction with prestin-based somatic motility. Both individual hair bundles and the cochlea as a whole operate near a dynamical instability, the Hopf bifurcation, which accounts for the cardinal features of the active process.
    Nature reviews Neuroscience 08/2014; DOI:10.1038/nrn3786 · 31.38 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014