Carly
Gelles
Compound Heterozygous Mouse Model of Progressive Hearing Loss
Abstract profile. Full document pending author claim.
Authors:
Carly Gelles, Penelope Toll, Eliot Shearer
Date Created:
2025-01-01
Course Title:
Professor:
Not specified
About Paper:
Cochlear implants (CIs), neural prostheses that directly stimulate To investigate the mechanisms underlying this form of hearing spiral ganglion neurons (SGNs), are the only current treatment for loss, we used CRISPR-Cas9-medY260X/A447Tonic gene editing severe to profound hearing loss caused by pathogenic variants in to generate a novel Tmprss3 mouse model. Auditory TMPRSS3, a type II transmembrane serine protease essential for function was assessed using auditory brainstem response (ABR). auditory function. However, individuals with TMPRSS3 mutations Cochlear structures, including inner and outer hair cells as often exhibit worse CI outcomes than those with other genetic well as Type I and Type II SGNs, were analyzed using Y260X/A447T causes of hearing loss. Notably, variants in genes primarily immunohistochemistry. Tmprss3 mice exhibited normal expressed in SGNs tend to correlate with poorer CI performance hair cell development and ABR thresholds through four months than mutations affecting only hair cells, suggesting that SGN of age. By five months, ABR thresholds were elevated compared dysfunction may underlie the auditory phenotype in TMPRSS3- to wild-type levels, with minimal hair cell loss observed between related hearing loss. three to eight months. Ongoing studies are evaluating SGN The TMPRSS3 Y260X nonsense mutation has been well densityacrossdevelopmentalstagestodeterminewhetherneuronal characterized and causes rapid postnatal hair cell degeneration anddegeneration contributes to the observed auditory decline. profound hearing loss in homozygous mouse models. In contrast, These investigations aim to clarify whether progressive SGN loss, the compound heterozygous Y260X/A447T mouse genotype, particularly of Type II neurons, plays a key role in TMPRSS3- which models the human p.His70ThrfsTer/p.Ala425Thr genotype associated hearing loss and may help explain reduced CI efficacy identified in a pediatric patient at Boston Children’s Hospital witin affected individuals. Understanding these mechanisms could progressive hearing loss, remains poorly understood. inform the development of targeted therapeutic strategies beyond cochlear implantation.
Abstract:
Cochlear implants (CIs), neural prostheses that directly stimulate To investigate the mechanisms underlying this form of hearing spiral ganglion neurons (SGNs), are the only current treatment for loss, we used CRISPR-Cas9-medY260X/A447Tonic gene editing severe to profound hearing loss caused by pathogenic variants in to generate a novel Tmprss3 mouse model. Auditory TMPRSS3, a type II transmembrane serine protease essential for function was assessed using auditory brainstem response (ABR). auditory function. However, individuals with TMPRSS3 mutations Cochlear structures, including inner and outer hair cells as often exhibit worse CI outcomes than those with other genetic well as Type I and Type II SGNs, were analyzed using Y260X/A447T causes of hearing loss. Notably, variants in genes primarily immunohistochemistry. Tmprss3 mice exhibited normal expressed in SGNs tend to correlate with poorer CI performance hair cell development and ABR thresholds through four months than mutations affecting only hair cells, suggesting that SGN of age. By five months, ABR thresholds were elevated compared dysfunction may underlie the auditory phenotype in TMPRSS3- to wild-type levels, with minimal hair cell loss observed between related hearing loss. three to eight months. Ongoing studies are evaluating SGN The TMPRSS3 Y260X nonsense mutation has been well densityacrossdevelopmentalstagestodeterminewhetherneuronal characterized and causes rapid postnatal hair cell degeneration anddegeneration contributes to the observed auditory decline. profound hearing loss in homozygous mouse models. In contrast, These investigations aim to clarify whether progressive SGN loss, the compound heterozygous Y260X/A447T mouse genotype, particularly of Type II neurons, plays a key role in TMPRSS3- which models the human p.His70ThrfsTer/p.Ala425Thr genotype associated hearing loss and may help explain reduced CI efficacy identified in a pediatric patient at Boston Children’s Hospital witin affected individuals. Understanding these mechanisms could progressive hearing loss, remains poorly understood. inform the development of targeted therapeutic strategies beyond cochlear implantation.
Source:
Harvard / Harvard College | Cabot House | English | 2027 / 2025
Topics:
loss, hearing, tmprss3, auditory, hair, cell, mouse, model, type, progressive, cochlear, sgns
