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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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Analysis of Gipc3 transgenic mice.(a) ABR thresholds (dBSPL) for click and pure tone pips at 8, 16 and 32 kHz are given in bars as mean±s.d. for backcross progeny tg(+/−) G/A (green, n=20), tg+A/A (blue, n=36) and tg-A/A (red, n=37). Green bars represent pooled data from backcross mice that were either positive or negative (+/−) for the transgene. (b) Audiogenic seizure susceptibility of tg(+/−) G/A (green symbol, n=10), tg+A/A (blue, n=) and tg-A/A (red, n=16) was assessed at 3 weeks of age using white noise stimuli (90, 100 and 110 dBSPL; dotted lines). Each circle represents one measurement and lines indicate the mean of the seizure latency of each genotype in seconds. **P<0.01; ***P<0.001.
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f3: Analysis of Gipc3 transgenic mice.(a) ABR thresholds (dBSPL) for click and pure tone pips at 8, 16 and 32 kHz are given in bars as mean±s.d. for backcross progeny tg(+/−) G/A (green, n=20), tg+A/A (blue, n=36) and tg-A/A (red, n=37). Green bars represent pooled data from backcross mice that were either positive or negative (+/−) for the transgene. (b) Audiogenic seizure susceptibility of tg(+/−) G/A (green symbol, n=10), tg+A/A (blue, n=) and tg-A/A (red, n=16) was assessed at 3 weeks of age using white noise stimuli (90, 100 and 110 dBSPL; dotted lines). Each circle represents one measurement and lines indicate the mean of the seizure latency of each genotype in seconds. **P<0.01; ***P<0.001.

Mentions: To further test that the 343G>A mutation in Gipc3 causes the ahl5 and jams1 phenotypes, we generated transgenic animals expressing Gipc3. Transgenic mice that were backcrossed to BLSW (N2–N3) were phenotyped using ABR at 6–8 weeks of age. In the control groups, Gipc3343G/A heterozygotes, irrespective of the presence or absence of the transgene (tg(+/−)G/A), expressed normal hearing thresholds (Fig. 3a and Supplementary Table S1) and Gipc3343A/A homozygotes without the transgene (tg-A/A) exhibited the hearing loss characteristic of the ahl5 phenotype. Interestingly, Gipc3343A/A homozygotes with the transgene (tg+A/A) showed hearing thresholds to the click, 8 and 16 kHz stimulus that were significantly lower than those of the tg-A/A mice. Furthermore, those thresholds were in the normal range and did not differ from those of the tg(+/−)G/A heterozygotes (P>0.05). For the 32 kHz stimulus tg+A/A mice had thresholds that were elevated compared with tg(+/−)G/A heterozygotes (71±9 dBSPL; P<0.001), although these thresholds were still lower than those of tg-A/A (92±8 dBSPL). Next, transgenic and non-transgenic N2–N3 backcross mice were exposed to white noise at 3 weeks of age. Gipc3343A/A homozygotes without the transgene (tg-A/A) reacted instantly at the 90 dBSPL stimulus with severe convulsions with an average latency period of 24 s. In contrast, Gipc3343A/A homozygotes with the transgene (tg+A/A) showed a significant delay (108 s); none of the animals seized at the 90 dB stimulus and two animals showed a complete resistance (Fig. 3b). Gipc3343G/A heterozygotes (tg(+/−)G/A) did not show any signs of seizing activity after 180 s of stimulation. In conclusion, the Gipc3 transgene rescued the ahl5 hearing deficit and jams1 audiogenic seizure susceptibility in Gipc3343A/A homozygotes.


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)

Analysis of Gipc3 transgenic mice.(a) ABR thresholds (dBSPL) for click and pure tone pips at 8, 16 and 32 kHz are given in bars as mean±s.d. for backcross progeny tg(+/−) G/A (green, n=20), tg+A/A (blue, n=36) and tg-A/A (red, n=37). Green bars represent pooled data from backcross mice that were either positive or negative (+/−) for the transgene. (b) Audiogenic seizure susceptibility of tg(+/−) G/A (green symbol, n=10), tg+A/A (blue, n=) and tg-A/A (red, n=16) was assessed at 3 weeks of age using white noise stimuli (90, 100 and 110 dBSPL; dotted lines). Each circle represents one measurement and lines indicate the mean of the seizure latency of each genotype in seconds. **P<0.01; ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Analysis of Gipc3 transgenic mice.(a) ABR thresholds (dBSPL) for click and pure tone pips at 8, 16 and 32 kHz are given in bars as mean±s.d. for backcross progeny tg(+/−) G/A (green, n=20), tg+A/A (blue, n=36) and tg-A/A (red, n=37). Green bars represent pooled data from backcross mice that were either positive or negative (+/−) for the transgene. (b) Audiogenic seizure susceptibility of tg(+/−) G/A (green symbol, n=10), tg+A/A (blue, n=) and tg-A/A (red, n=16) was assessed at 3 weeks of age using white noise stimuli (90, 100 and 110 dBSPL; dotted lines). Each circle represents one measurement and lines indicate the mean of the seizure latency of each genotype in seconds. **P<0.01; ***P<0.001.
Mentions: To further test that the 343G>A mutation in Gipc3 causes the ahl5 and jams1 phenotypes, we generated transgenic animals expressing Gipc3. Transgenic mice that were backcrossed to BLSW (N2–N3) were phenotyped using ABR at 6–8 weeks of age. In the control groups, Gipc3343G/A heterozygotes, irrespective of the presence or absence of the transgene (tg(+/−)G/A), expressed normal hearing thresholds (Fig. 3a and Supplementary Table S1) and Gipc3343A/A homozygotes without the transgene (tg-A/A) exhibited the hearing loss characteristic of the ahl5 phenotype. Interestingly, Gipc3343A/A homozygotes with the transgene (tg+A/A) showed hearing thresholds to the click, 8 and 16 kHz stimulus that were significantly lower than those of the tg-A/A mice. Furthermore, those thresholds were in the normal range and did not differ from those of the tg(+/−)G/A heterozygotes (P>0.05). For the 32 kHz stimulus tg+A/A mice had thresholds that were elevated compared with tg(+/−)G/A heterozygotes (71±9 dBSPL; P<0.001), although these thresholds were still lower than those of tg-A/A (92±8 dBSPL). Next, transgenic and non-transgenic N2–N3 backcross mice were exposed to white noise at 3 weeks of age. Gipc3343A/A homozygotes without the transgene (tg-A/A) reacted instantly at the 90 dBSPL stimulus with severe convulsions with an average latency period of 24 s. In contrast, Gipc3343A/A homozygotes with the transgene (tg+A/A) showed a significant delay (108 s); none of the animals seized at the 90 dB stimulus and two animals showed a complete resistance (Fig. 3b). Gipc3343G/A heterozygotes (tg(+/−)G/A) did not show any signs of seizing activity after 180 s of stimulation. In conclusion, the Gipc3 transgene rescued the ahl5 hearing deficit and jams1 audiogenic seizure susceptibility in Gipc3343A/A homozygotes.

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