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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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Audiogenic seizure progression correlates with ABR wave I amplitude.(a) Shown are audiogenic seizure latencies (seconds) after white noise stimulation at 90, 100 and 110 dBSPL (dotted lines) of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥3) as function of weeks of age. Each circle represents one measurement and the line indicates the mean of the response. (b) Shown are ABR wave I amplitudes obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (c, d) Shown are ABR amplitudes for waves I through V following a 100-dBSPL click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥10) at 2 (c) and 6 (d) weeks of age. Data are given as mean±s.d. (e) Shown are ABR wave I latencies obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (f) ABR thresholds shown are obtained with a click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥2) as function of weeks of age. Data are given as mean±s.d. Dotted connecting lines: linear regression lines. NS P>0.05; *P<0.05; **P<0.01; ***P<0.001, ANOVA. NS, not significant.
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f8: Audiogenic seizure progression correlates with ABR wave I amplitude.(a) Shown are audiogenic seizure latencies (seconds) after white noise stimulation at 90, 100 and 110 dBSPL (dotted lines) of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥3) as function of weeks of age. Each circle represents one measurement and the line indicates the mean of the response. (b) Shown are ABR wave I amplitudes obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (c, d) Shown are ABR amplitudes for waves I through V following a 100-dBSPL click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥10) at 2 (c) and 6 (d) weeks of age. Data are given as mean±s.d. (e) Shown are ABR wave I latencies obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (f) ABR thresholds shown are obtained with a click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥2) as function of weeks of age. Data are given as mean±s.d. Dotted connecting lines: linear regression lines. NS P>0.05; *P<0.05; **P<0.01; ***P<0.001, ANOVA. NS, not significant.

Mentions: To investigate the cause of the audiogenic seizure susceptibility and resistance, we correlated various ABR output parameters with seizure progression. Acoustic stimulation showed that BLSW mice were most susceptible to seizures between 2 and 4 weeks of age with mean seizure latencies of 40±42 s (n=19) and 89±32 s (n=21), respectively. Thereafter, latencies increased until animals became completely resistant at 6 weeks of age (180 s, n=15). Increases in seizure latencies were significant between 3 and 5 weeks and between 4 and 6 weeks of age (Fig. 8a).


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)

Audiogenic seizure progression correlates with ABR wave I amplitude.(a) Shown are audiogenic seizure latencies (seconds) after white noise stimulation at 90, 100 and 110 dBSPL (dotted lines) of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥3) as function of weeks of age. Each circle represents one measurement and the line indicates the mean of the response. (b) Shown are ABR wave I amplitudes obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (c, d) Shown are ABR amplitudes for waves I through V following a 100-dBSPL click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥10) at 2 (c) and 6 (d) weeks of age. Data are given as mean±s.d. (e) Shown are ABR wave I latencies obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (f) ABR thresholds shown are obtained with a click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥2) as function of weeks of age. Data are given as mean±s.d. Dotted connecting lines: linear regression lines. NS P>0.05; *P<0.05; **P<0.01; ***P<0.001, ANOVA. NS, not significant.
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Related In: Results  -  Collection

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f8: Audiogenic seizure progression correlates with ABR wave I amplitude.(a) Shown are audiogenic seizure latencies (seconds) after white noise stimulation at 90, 100 and 110 dBSPL (dotted lines) of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥3) as function of weeks of age. Each circle represents one measurement and the line indicates the mean of the response. (b) Shown are ABR wave I amplitudes obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (c, d) Shown are ABR amplitudes for waves I through V following a 100-dBSPL click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥10) at 2 (c) and 6 (d) weeks of age. Data are given as mean±s.d. (e) Shown are ABR wave I latencies obtained with a 100-dBSPL click stimulus of BLSW (red, n≥8) and C3HeB/FeJ (blue, n≥9) as function of weeks of age. Data are given as mean±s.d. (f) ABR thresholds shown are obtained with a click stimulus of BLSW (red, n≥9) and C3HeB/FeJ (blue, n≥2) as function of weeks of age. Data are given as mean±s.d. Dotted connecting lines: linear regression lines. NS P>0.05; *P<0.05; **P<0.01; ***P<0.001, ANOVA. NS, not significant.
Mentions: To investigate the cause of the audiogenic seizure susceptibility and resistance, we correlated various ABR output parameters with seizure progression. Acoustic stimulation showed that BLSW mice were most susceptible to seizures between 2 and 4 weeks of age with mean seizure latencies of 40±42 s (n=19) and 89±32 s (n=21), respectively. Thereafter, latencies increased until animals became completely resistant at 6 weeks of age (180 s, n=15). Increases in seizure latencies were significant between 3 and 5 weeks and between 4 and 6 weeks of age (Fig. 8a).

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