Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation

Ruishuang Geng, Scott F. Geller, Toshinori Hayashi, Catherine A. Ray, Thomas A. Reh, Olivia Bermingham-McDonogh, Sherri M. Jones, Charles G. Wright, Sami Melki, Yoshikazu Imanishi, Krzysztof Palczewski, Kumar N. Alagramam, John G. Flannery

Research output: Contribution to journalArticle

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Abstract

Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1-/-) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1-/- mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14-P21), Clrn1-/- mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, ∼70% of Clrn1-/- mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1-/- mice. Vestibular function in Clrn1-/- mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1-/- mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation.

Original languageEnglish (US)
Pages (from-to)2748-2760
Number of pages13
JournalHuman Molecular Genetics
Volume18
Issue number15
DOIs
StatePublished - 2009

Fingerprint

Usher Syndromes
Outer Auditory Hair Cells
Genes
Cochlea
Brain Stem Auditory Evoked Potentials
Inner Ear
Inner Auditory Hair Cells
Auditory Hair Cells
Deaf-Blind Disorders
Vestibular Hair Cells
Stereocilia
Ear Diseases
Phenotype
Alopecia
Hearing Loss
Evoked Potentials
Knockout Mice
Animal Models
Parturition
Neurons

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Geng, R., Geller, S. F., Hayashi, T., Ray, C. A., Reh, T. A., Bermingham-McDonogh, O., ... Flannery, J. G. (2009). Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation. Human Molecular Genetics, 18(15), 2748-2760. https://doi.org/10.1093/hmg/ddp210

Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation. / Geng, Ruishuang; Geller, Scott F.; Hayashi, Toshinori; Ray, Catherine A.; Reh, Thomas A.; Bermingham-McDonogh, Olivia; Jones, Sherri M.; Wright, Charles G.; Melki, Sami; Imanishi, Yoshikazu; Palczewski, Krzysztof; Alagramam, Kumar N.; Flannery, John G.

In: Human Molecular Genetics, Vol. 18, No. 15, 2009, p. 2748-2760.

Research output: Contribution to journalArticle

Geng, R, Geller, SF, Hayashi, T, Ray, CA, Reh, TA, Bermingham-McDonogh, O, Jones, SM, Wright, CG, Melki, S, Imanishi, Y, Palczewski, K, Alagramam, KN & Flannery, JG 2009, 'Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation', Human Molecular Genetics, vol. 18, no. 15, pp. 2748-2760. https://doi.org/10.1093/hmg/ddp210
Geng, Ruishuang ; Geller, Scott F. ; Hayashi, Toshinori ; Ray, Catherine A. ; Reh, Thomas A. ; Bermingham-McDonogh, Olivia ; Jones, Sherri M. ; Wright, Charles G. ; Melki, Sami ; Imanishi, Yoshikazu ; Palczewski, Krzysztof ; Alagramam, Kumar N. ; Flannery, John G. / Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 15. pp. 2748-2760.
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abstract = "Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1-/-) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1-/- mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14-P21), Clrn1-/- mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, ∼70{\%} of Clrn1-/- mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1-/- mice. Vestibular function in Clrn1-/- mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1-/- mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation.",
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AU - Hayashi, Toshinori

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AU - Reh, Thomas A.

AU - Bermingham-McDonogh, Olivia

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AU - Wright, Charles G.

AU - Melki, Sami

AU - Imanishi, Yoshikazu

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AU - Alagramam, Kumar N.

AU - Flannery, John G.

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AB - Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1-/-) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1-/- mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14-P21), Clrn1-/- mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, ∼70% of Clrn1-/- mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1-/- mice. Vestibular function in Clrn1-/- mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1-/- mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation.

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