title: A novel otoferlin splice-site mutation in siblings with auditory neuropathy spectrum disorder.
abstract: We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered.
authors.affiliation: Departments of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisc., USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Runge
authors.forename: Christy B
authors.initials: CB
authors.lastname: Erbe
authors.forename: Mark T
authors.initials: MT
authors.lastname: McNally
authors.forename: Courtney
authors.initials: C
authors.lastname: Van Dusen
authors.forename: David R
authors.initials: DR
authors.lastname: Friedland
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Kerschner
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D019929:Cochlear Implantation; D003054:Cochlear Implants; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006313:Hearing Loss, Central / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D006319:Hearing Loss, Sensorineural / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D035781:Siblings; D013067:Speech Perception / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C118457:OTOF protein, human; D022821:RNA Splice Sites