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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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Related in: MedlinePlus

Stereocilia and cochlear pathology in BLSW mice.(a) Confocal images of C3HeB/FeJ and BLSW phalloidin-stained organs of Corti at P3 and P5 from the mid-apical and basal turn are shown. Note the compromised hair bundle structure of OHC (white arrow) and collapsed bundle of IHC (arrowhead) in BLSW mice. Scale bar, 5 μm. (b) Shown are scanning electron microscopy images of OHC (arrow) and IHC (arrowhead) stereocilia bundles at P14. Compare the inward-bended stereocilia on BLSW OHCs to the organized and upright standing bundles in C3HeB/FeJ. Compare the sparse IHC stereocilia in BLSW with the dense bundle in C3HeB/FeJ. Scale bar, 2 μm. (c) Shown are confocal images of IHC stereocilia bundles at P21. Note the thinner (arrow) and shorter (star) stereocilia in BLSW. Scale bar, 5 μm. (d) Images of tolouidine-stained cross-sections of the organ of Corti and spiral ganglion are shown. Age and region of the cochlea is indicated. Note the normal appearance of organ of Corti (arrows point to OHC and arrowhead to IHC) and spiral ganglion neurons (arrow) in 8-week-old BLSW mice, but base to mid–apex degeneration (red star) in 52-week-old BLSW cochleae. Scale bar, 20 μm (top panel) and 50 μm (bottom panel).
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f5: Stereocilia and cochlear pathology in BLSW mice.(a) Confocal images of C3HeB/FeJ and BLSW phalloidin-stained organs of Corti at P3 and P5 from the mid-apical and basal turn are shown. Note the compromised hair bundle structure of OHC (white arrow) and collapsed bundle of IHC (arrowhead) in BLSW mice. Scale bar, 5 μm. (b) Shown are scanning electron microscopy images of OHC (arrow) and IHC (arrowhead) stereocilia bundles at P14. Compare the inward-bended stereocilia on BLSW OHCs to the organized and upright standing bundles in C3HeB/FeJ. Compare the sparse IHC stereocilia in BLSW with the dense bundle in C3HeB/FeJ. Scale bar, 2 μm. (c) Shown are confocal images of IHC stereocilia bundles at P21. Note the thinner (arrow) and shorter (star) stereocilia in BLSW. Scale bar, 5 μm. (d) Images of tolouidine-stained cross-sections of the organ of Corti and spiral ganglion are shown. Age and region of the cochlea is indicated. Note the normal appearance of organ of Corti (arrows point to OHC and arrowhead to IHC) and spiral ganglion neurons (arrow) in 8-week-old BLSW mice, but base to mid–apex degeneration (red star) in 52-week-old BLSW cochleae. Scale bar, 20 μm (top panel) and 50 μm (bottom panel).

Mentions: The high-to-low frequency progression of the hearing loss suggested a histopathology in the organ of Corti. By confocal and scanning electron microscopy we observed an irregular structure of the stereocilia bundle of OHC and inner hair cells (IHC). Starting from postnatal day 3 (P3) onwards, OHC bundles were slightly disoriented and smaller, with bent lateral edges and a rounded apical pole (Fig. 5a,b). The hair bundle of IHC appeared less rigid and sparse (Fig. 5a,b) and at P21 stereocilia were thinner and at times also shorter (Fig. 5c). Stereocilia bundles at the base and mid-apical region were present and were affected to a similar degree. Histological sections of 8-week-old BLSW ears revealed a normal morphology of the organ of Corti and the spiral ganglion. At 52 weeks of age, there was a significant degeneration of the organ of Corti starting at the base and progressing towards the apex. Concomitantly, the spiral ganglion exhibited a severe loss of neurons that was most obvious at the base and the mid-apical region of the cochlea. The organ of Corti and spiral ganglion at the apex were of normal appearance (Fig. 5d). Together, these data suggest that Gipc3 is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.


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)

Stereocilia and cochlear pathology in BLSW mice.(a) Confocal images of C3HeB/FeJ and BLSW phalloidin-stained organs of Corti at P3 and P5 from the mid-apical and basal turn are shown. Note the compromised hair bundle structure of OHC (white arrow) and collapsed bundle of IHC (arrowhead) in BLSW mice. Scale bar, 5 μm. (b) Shown are scanning electron microscopy images of OHC (arrow) and IHC (arrowhead) stereocilia bundles at P14. Compare the inward-bended stereocilia on BLSW OHCs to the organized and upright standing bundles in C3HeB/FeJ. Compare the sparse IHC stereocilia in BLSW with the dense bundle in C3HeB/FeJ. Scale bar, 2 μm. (c) Shown are confocal images of IHC stereocilia bundles at P21. Note the thinner (arrow) and shorter (star) stereocilia in BLSW. Scale bar, 5 μm. (d) Images of tolouidine-stained cross-sections of the organ of Corti and spiral ganglion are shown. Age and region of the cochlea is indicated. Note the normal appearance of organ of Corti (arrows point to OHC and arrowhead to IHC) and spiral ganglion neurons (arrow) in 8-week-old BLSW mice, but base to mid–apex degeneration (red star) in 52-week-old BLSW cochleae. Scale bar, 20 μm (top panel) and 50 μm (bottom panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f5: Stereocilia and cochlear pathology in BLSW mice.(a) Confocal images of C3HeB/FeJ and BLSW phalloidin-stained organs of Corti at P3 and P5 from the mid-apical and basal turn are shown. Note the compromised hair bundle structure of OHC (white arrow) and collapsed bundle of IHC (arrowhead) in BLSW mice. Scale bar, 5 μm. (b) Shown are scanning electron microscopy images of OHC (arrow) and IHC (arrowhead) stereocilia bundles at P14. Compare the inward-bended stereocilia on BLSW OHCs to the organized and upright standing bundles in C3HeB/FeJ. Compare the sparse IHC stereocilia in BLSW with the dense bundle in C3HeB/FeJ. Scale bar, 2 μm. (c) Shown are confocal images of IHC stereocilia bundles at P21. Note the thinner (arrow) and shorter (star) stereocilia in BLSW. Scale bar, 5 μm. (d) Images of tolouidine-stained cross-sections of the organ of Corti and spiral ganglion are shown. Age and region of the cochlea is indicated. Note the normal appearance of organ of Corti (arrows point to OHC and arrowhead to IHC) and spiral ganglion neurons (arrow) in 8-week-old BLSW mice, but base to mid–apex degeneration (red star) in 52-week-old BLSW cochleae. Scale bar, 20 μm (top panel) and 50 μm (bottom panel).
Mentions: The high-to-low frequency progression of the hearing loss suggested a histopathology in the organ of Corti. By confocal and scanning electron microscopy we observed an irregular structure of the stereocilia bundle of OHC and inner hair cells (IHC). Starting from postnatal day 3 (P3) onwards, OHC bundles were slightly disoriented and smaller, with bent lateral edges and a rounded apical pole (Fig. 5a,b). The hair bundle of IHC appeared less rigid and sparse (Fig. 5a,b) and at P21 stereocilia were thinner and at times also shorter (Fig. 5c). Stereocilia bundles at the base and mid-apical region were present and were affected to a similar degree. Histological sections of 8-week-old BLSW ears revealed a normal morphology of the organ of Corti and the spiral ganglion. At 52 weeks of age, there was a significant degeneration of the organ of Corti starting at the base and progressing towards the apex. Concomitantly, the spiral ganglion exhibited a severe loss of neurons that was most obvious at the base and the mid-apical region of the cochlea. The organ of Corti and spiral ganglion at the apex were of normal appearance (Fig. 5d). Together, these data suggest that Gipc3 is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion.

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