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A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9.
Hear Res 2007; 234(1-2):21-8HR

Abstract

Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analyses of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otof(deaf5Jcs). The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wildtype mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wildtype mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells.

Authors+Show Affiliations

The Jackson Laboratory, Bar Harbor, ME 04609, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17967520

Citation

Longo-Guess, Chantal, et al. "A Missense Mutation in the Conserved C2B Domain of Otoferlin Causes Deafness in a New Mouse Model of DFNB9." Hearing Research, vol. 234, no. 1-2, 2007, pp. 21-8.
Longo-Guess C, Gagnon LH, Bergstrom DE, et al. A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9. Hear Res. 2007;234(1-2):21-8.
Longo-Guess, C., Gagnon, L. H., Bergstrom, D. E., & Johnson, K. R. (2007). A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9. Hearing Research, 234(1-2), pp. 21-8.
Longo-Guess C, et al. A Missense Mutation in the Conserved C2B Domain of Otoferlin Causes Deafness in a New Mouse Model of DFNB9. Hear Res. 2007;234(1-2):21-8. PubMed PMID: 17967520.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9. AU - Longo-Guess,Chantal, AU - Gagnon,Leona H, AU - Bergstrom,David E, AU - Johnson,Kenneth R, Y1 - 2007/09/29/ PY - 2007/07/25/received PY - 2007/09/04/revised PY - 2007/09/07/accepted PY - 2007/10/31/pubmed PY - 2008/2/1/medline PY - 2007/10/31/entrez SP - 21 EP - 8 JF - Hearing research JO - Hear. Res. VL - 234 IS - 1-2 N2 - Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analyses of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otof(deaf5Jcs). The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wildtype mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wildtype mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells. SN - 0378-5955 UR - https://www.unboundmedicine.com/medline/citation/17967520/A_missense_mutation_in_the_conserved_C2B_domain_of_otoferlin_causes_deafness_in_a_new_mouse_model_of_DFNB9_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5955(07)00214-6 DB - PRIME DP - Unbound Medicine ER -