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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.

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Sensorineural hearing loss and audiogenic seizures in BLSW.(a) ABR thresholds (dBSPL) of BLSW at 4 (orange symbol, n=18) and 52 (red, n=20) weeks age compared with 4-week-old C3HeB/FeJ (blue, n=9) are given as mean±s.d. (b) ABR thresholds (dBSPL) at the 16k Hz stimulus in 2- (n=6) and 12-months-old (n=17) BLSW.CAST-+/+ (blue), and in 2-month-old BLSW.CAST-+/ahl5 (green, n=52), and 2- (n=9) and 12-months-old (n=20) BLSW (red) are given as mean±s.d. ABR thresholds in 12-month-old females (12f, n=30) and males (12 m, n=30) are given. NS P>0.05, ***P<0.001 (ANOVA). (c) DPOAE levels (dBSPL) at the 2f1-f2 frequency are plotted against the f2 frequency (kHz) for 55 dBSPL (left), 65 dBSPL (middle) and 75 dBSPL (right) L2 levels. Emission levels relative to noise floor of C3HeB/FeJ (blue, n=25) and BLSW (red, n=16) mice at 4 weeks of age are given as mean±s.e.m. (d) Endocochlear potential measurements of C3HeB/FeJ (blue, n=5) and BLSW (red, n=15) mice. Each circle refers to one measurement and the lines indicate the mean in each strain. Values are given in millivolt (mV). (e) Audiogenic seizure susceptibility of C3HeB/FeJ (blue, n=5), BLSW (dark red, n=14) and congenic BLSW.CAST-+/+ (blue, n=9), BLSW.CAST-+/ahl5 (green, n=23), BLSW.CAST-ahl5/ahl5 (light red, n=34) at 3 weeks of age using white noise stimuli of 90, 100 and 110 dBSPL (dotted lines). Each circle represents one animal and lines indicate the mean of the seizure latency of each strain in seconds. NS P>0.05; ***P<0.001. NS, not significant.
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f2: Sensorineural hearing loss and audiogenic seizures in BLSW.(a) ABR thresholds (dBSPL) of BLSW at 4 (orange symbol, n=18) and 52 (red, n=20) weeks age compared with 4-week-old C3HeB/FeJ (blue, n=9) are given as mean±s.d. (b) ABR thresholds (dBSPL) at the 16k Hz stimulus in 2- (n=6) and 12-months-old (n=17) BLSW.CAST-+/+ (blue), and in 2-month-old BLSW.CAST-+/ahl5 (green, n=52), and 2- (n=9) and 12-months-old (n=20) BLSW (red) are given as mean±s.d. ABR thresholds in 12-month-old females (12f, n=30) and males (12 m, n=30) are given. NS P>0.05, ***P<0.001 (ANOVA). (c) DPOAE levels (dBSPL) at the 2f1-f2 frequency are plotted against the f2 frequency (kHz) for 55 dBSPL (left), 65 dBSPL (middle) and 75 dBSPL (right) L2 levels. Emission levels relative to noise floor of C3HeB/FeJ (blue, n=25) and BLSW (red, n=16) mice at 4 weeks of age are given as mean±s.e.m. (d) Endocochlear potential measurements of C3HeB/FeJ (blue, n=5) and BLSW (red, n=15) mice. Each circle refers to one measurement and the lines indicate the mean in each strain. Values are given in millivolt (mV). (e) Audiogenic seizure susceptibility of C3HeB/FeJ (blue, n=5), BLSW (dark red, n=14) and congenic BLSW.CAST-+/+ (blue, n=9), BLSW.CAST-+/ahl5 (green, n=23), BLSW.CAST-ahl5/ahl5 (light red, n=34) at 3 weeks of age using white noise stimuli of 90, 100 and 110 dBSPL (dotted lines). Each circle represents one animal and lines indicate the mean of the seizure latency of each strain in seconds. NS P>0.05; ***P<0.001. NS, not significant.

Mentions: At 4 weeks of age, BLSW mice showed a moderate hearing impairment with mean thresholds significantly elevated for the click, 8, 16 and 32 kHz stimuli (68±7, 41±6, 41±5 and 85±5 dBSPL) compared with thresholds of 4-week-old normal hearing C3HeB/FeJ mice (P<0.001). At 52 weeks of age, BLSW mice exhibited a profound hearing loss that progressed from higher to lower test frequencies. The increase in hearing thresholds was most pronounced at 16 kHz with a shift of 48 dBSPL over the threshold of 4-week-old BLSW mice (Fig. 2a).


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)

Sensorineural hearing loss and audiogenic seizures in BLSW.(a) ABR thresholds (dBSPL) of BLSW at 4 (orange symbol, n=18) and 52 (red, n=20) weeks age compared with 4-week-old C3HeB/FeJ (blue, n=9) are given as mean±s.d. (b) ABR thresholds (dBSPL) at the 16k Hz stimulus in 2- (n=6) and 12-months-old (n=17) BLSW.CAST-+/+ (blue), and in 2-month-old BLSW.CAST-+/ahl5 (green, n=52), and 2- (n=9) and 12-months-old (n=20) BLSW (red) are given as mean±s.d. ABR thresholds in 12-month-old females (12f, n=30) and males (12 m, n=30) are given. NS P>0.05, ***P<0.001 (ANOVA). (c) DPOAE levels (dBSPL) at the 2f1-f2 frequency are plotted against the f2 frequency (kHz) for 55 dBSPL (left), 65 dBSPL (middle) and 75 dBSPL (right) L2 levels. Emission levels relative to noise floor of C3HeB/FeJ (blue, n=25) and BLSW (red, n=16) mice at 4 weeks of age are given as mean±s.e.m. (d) Endocochlear potential measurements of C3HeB/FeJ (blue, n=5) and BLSW (red, n=15) mice. Each circle refers to one measurement and the lines indicate the mean in each strain. Values are given in millivolt (mV). (e) Audiogenic seizure susceptibility of C3HeB/FeJ (blue, n=5), BLSW (dark red, n=14) and congenic BLSW.CAST-+/+ (blue, n=9), BLSW.CAST-+/ahl5 (green, n=23), BLSW.CAST-ahl5/ahl5 (light red, n=34) at 3 weeks of age using white noise stimuli of 90, 100 and 110 dBSPL (dotted lines). Each circle represents one animal and lines indicate the mean of the seizure latency of each strain in seconds. NS P>0.05; ***P<0.001. NS, not significant.
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f2: Sensorineural hearing loss and audiogenic seizures in BLSW.(a) ABR thresholds (dBSPL) of BLSW at 4 (orange symbol, n=18) and 52 (red, n=20) weeks age compared with 4-week-old C3HeB/FeJ (blue, n=9) are given as mean±s.d. (b) ABR thresholds (dBSPL) at the 16k Hz stimulus in 2- (n=6) and 12-months-old (n=17) BLSW.CAST-+/+ (blue), and in 2-month-old BLSW.CAST-+/ahl5 (green, n=52), and 2- (n=9) and 12-months-old (n=20) BLSW (red) are given as mean±s.d. ABR thresholds in 12-month-old females (12f, n=30) and males (12 m, n=30) are given. NS P>0.05, ***P<0.001 (ANOVA). (c) DPOAE levels (dBSPL) at the 2f1-f2 frequency are plotted against the f2 frequency (kHz) for 55 dBSPL (left), 65 dBSPL (middle) and 75 dBSPL (right) L2 levels. Emission levels relative to noise floor of C3HeB/FeJ (blue, n=25) and BLSW (red, n=16) mice at 4 weeks of age are given as mean±s.e.m. (d) Endocochlear potential measurements of C3HeB/FeJ (blue, n=5) and BLSW (red, n=15) mice. Each circle refers to one measurement and the lines indicate the mean in each strain. Values are given in millivolt (mV). (e) Audiogenic seizure susceptibility of C3HeB/FeJ (blue, n=5), BLSW (dark red, n=14) and congenic BLSW.CAST-+/+ (blue, n=9), BLSW.CAST-+/ahl5 (green, n=23), BLSW.CAST-ahl5/ahl5 (light red, n=34) at 3 weeks of age using white noise stimuli of 90, 100 and 110 dBSPL (dotted lines). Each circle represents one animal and lines indicate the mean of the seizure latency of each strain in seconds. NS P>0.05; ***P<0.001. NS, not significant.
Mentions: At 4 weeks of age, BLSW mice showed a moderate hearing impairment with mean thresholds significantly elevated for the click, 8, 16 and 32 kHz stimuli (68±7, 41±6, 41±5 and 85±5 dBSPL) compared with thresholds of 4-week-old normal hearing C3HeB/FeJ mice (P<0.001). At 52 weeks of age, BLSW mice exhibited a profound hearing loss that progressed from higher to lower test frequencies. The increase in hearing thresholds was most pronounced at 16 kHz with a shift of 48 dBSPL over the threshold of 4-week-old BLSW mice (Fig. 2a).

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