Limits...
Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K - Nat Commun (2011)

Bottom Line: A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents.The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons.Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

View Article: PubMed Central - PubMed

Affiliation: Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.

ABSTRACT
Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

Show MeSH

Related in: MedlinePlus

Electrophysiological measurements from BLSW and control mice.(a) Families of transduction currents recorded from OHC (n=8–11) and IHC (n=3–10) collected from the apical turn of BLSW and control mice at P6 and P12 are shown. The scale bar applies to all four families. The cells were voltage-clamped at −64 mV. The data shown at P6 are representative of the mean, whereas the data shown at P12 represent the largest currents obtained at that stage. (b) Summary of mean maximal currents recorded from a total of 62 hair cells of control (blue bars) and BLSW (red). The data were normalized to mean maximal control currents in each condition. Bars indicate mean±s.e.m.; **P<0.005; ***P<0.00005 (two-population t-test). (c) Families of voltage-dependent currents evoked by 50-msec steps that ranged between −124 and 96 mV in 20 mV increments. Currents were recorded from IHC at P6 (top panel) and at P13 (control, n=5) and P12 (BLSW, n=8, bottom panel). The scale bar applies to all current families. (d) Membrane potentials recorded in current-clamp mode in response to current steps at the amplitudes indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3105340&req=5

f7: Electrophysiological measurements from BLSW and control mice.(a) Families of transduction currents recorded from OHC (n=8–11) and IHC (n=3–10) collected from the apical turn of BLSW and control mice at P6 and P12 are shown. The scale bar applies to all four families. The cells were voltage-clamped at −64 mV. The data shown at P6 are representative of the mean, whereas the data shown at P12 represent the largest currents obtained at that stage. (b) Summary of mean maximal currents recorded from a total of 62 hair cells of control (blue bars) and BLSW (red). The data were normalized to mean maximal control currents in each condition. Bars indicate mean±s.e.m.; **P<0.005; ***P<0.00005 (two-population t-test). (c) Families of voltage-dependent currents evoked by 50-msec steps that ranged between −124 and 96 mV in 20 mV increments. Currents were recorded from IHC at P6 (top panel) and at P13 (control, n=5) and P12 (BLSW, n=8, bottom panel). The scale bar applies to all current families. (d) Membrane potentials recorded in current-clamp mode in response to current steps at the amplitudes indicated.

Mentions: The compromised structure of the stereocilia bundle suggested a defect in mechanotransduction. At P6, we found no difference in transduction currents recorded from OHCs and IHCs between BLSW and Swiss Webster control mice. The mean maximal amplitudes of the transduction currents operating range and adaptation time constants were not significantly different between BLSW and control hair cells. However, by P12 we observed a significant reduction in the maximal transduction current amplitude in both IHCs and OHCs. The mean maximal transduction currents recorded from IHCs and OHCs of P12-P14 BLSW mice were reduced by 57 and 71%, respectively, compared with control hair cells (Fig. 7a,b). This reduction likely accounts for the elevated hearing thresholds.


Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K - Nat Commun (2011)

Electrophysiological measurements from BLSW and control mice.(a) Families of transduction currents recorded from OHC (n=8–11) and IHC (n=3–10) collected from the apical turn of BLSW and control mice at P6 and P12 are shown. The scale bar applies to all four families. The cells were voltage-clamped at −64 mV. The data shown at P6 are representative of the mean, whereas the data shown at P12 represent the largest currents obtained at that stage. (b) Summary of mean maximal currents recorded from a total of 62 hair cells of control (blue bars) and BLSW (red). The data were normalized to mean maximal control currents in each condition. Bars indicate mean±s.e.m.; **P<0.005; ***P<0.00005 (two-population t-test). (c) Families of voltage-dependent currents evoked by 50-msec steps that ranged between −124 and 96 mV in 20 mV increments. Currents were recorded from IHC at P6 (top panel) and at P13 (control, n=5) and P12 (BLSW, n=8, bottom panel). The scale bar applies to all current families. (d) Membrane potentials recorded in current-clamp mode in response to current steps at the amplitudes indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105340&req=5

f7: Electrophysiological measurements from BLSW and control mice.(a) Families of transduction currents recorded from OHC (n=8–11) and IHC (n=3–10) collected from the apical turn of BLSW and control mice at P6 and P12 are shown. The scale bar applies to all four families. The cells were voltage-clamped at −64 mV. The data shown at P6 are representative of the mean, whereas the data shown at P12 represent the largest currents obtained at that stage. (b) Summary of mean maximal currents recorded from a total of 62 hair cells of control (blue bars) and BLSW (red). The data were normalized to mean maximal control currents in each condition. Bars indicate mean±s.e.m.; **P<0.005; ***P<0.00005 (two-population t-test). (c) Families of voltage-dependent currents evoked by 50-msec steps that ranged between −124 and 96 mV in 20 mV increments. Currents were recorded from IHC at P6 (top panel) and at P13 (control, n=5) and P12 (BLSW, n=8, bottom panel). The scale bar applies to all current families. (d) Membrane potentials recorded in current-clamp mode in response to current steps at the amplitudes indicated.
Mentions: The compromised structure of the stereocilia bundle suggested a defect in mechanotransduction. At P6, we found no difference in transduction currents recorded from OHCs and IHCs between BLSW and Swiss Webster control mice. The mean maximal amplitudes of the transduction currents operating range and adaptation time constants were not significantly different between BLSW and control hair cells. However, by P12 we observed a significant reduction in the maximal transduction current amplitude in both IHCs and OHCs. The mean maximal transduction currents recorded from IHCs and OHCs of P12-P14 BLSW mice were reduced by 57 and 71%, respectively, compared with control hair cells (Fig. 7a,b). This reduction likely accounts for the elevated hearing thresholds.

Bottom Line: A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents.The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons.Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

View Article: PubMed Central - PubMed

Affiliation: Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.

ABSTRACT
Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

Show MeSH
Related in: MedlinePlus