title: Mutation in the kv3.3 voltage-gated potassium channel causing spinocerebellar ataxia 13 disrupts sound-localization mechanisms.
abstract: Normal sound localization requires precise comparisons of sound timing and pressure levels between the two ears. The primary localization cues are interaural time differences, ITD, and interaural level differences, ILD. Voltage-gated potassium channels, including Kv3.3, are highly expressed in the auditory brainstem and are thought to underlie the exquisite temporal precision and rapid spike rates that characterize brainstem binaural pathways. An autosomal dominant mutation in the gene encoding Kv3.3 has been demonstrated in a large Filipino kindred manifesting as spinocerebellar ataxia type 13 (SCA13). This kindred provides a rare opportunity to test in vivo the importance of a specific channel subunit for human hearing. Here, we demonstrate psychophysically that individuals with the mutant allele exhibit profound deficits in both ITD and ILD sensitivity, despite showing no obvious impairment in pure-tone sensitivity with either ear. Surprisingly, several individuals exhibited the auditory deficits even though they were pre-symptomatic for SCA13. We would expect that impairments of binaural processing as great as those observed in this family would result in prominent deficits in localization of sound sources and in loss of the "spatial release from masking" that aids in understanding speech in the presence of competing sounds.
authors.affiliation: Departments of Otolaryngology, Neurobiology & Behavior, Cognitive Sciences and Biomedical Engineering and Center for Hearing Research, University of California Irvine, Irvine, California, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Middlebrooks
authors.forename: Harry S
authors.initials: HS
authors.lastname: Nick
authors.forename: S H
authors.initials: SH
authors.lastname: Subramony
authors.forename: Joel
authors.initials: J
authors.lastname: Advincula
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Rosales
authors.forename: Lillian V
authors.initials: LV
authors.lastname: Lee
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Michael F
authors.initials: MF
authors.lastname: Waters
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001309:Auditory Threshold; D002648:Child; D003463:Cues; D005260:Female; D005799:Genes, Dominant; D006309:Hearing / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051670:Shaw Potassium Channels / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013017:Sound Localization; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels