Beethoven, a mouse model for dominant, progressive hearing loss DFNA36

Vreugde, Sarah; Erven, Alexandra; Kros, Corné J.; Marcotti, Walter; Fuchs, Helmut; Kurima, Kiyoto; Wilcox, Edward R.; Friedman, Thomas B.; Griffith, Andrew J.; Balling, Rudi; Angelis, Martin Hrabé de; Avraham, Karen B.; Steel, Karen P.

doi:10.1038/ng848

Cited by 242 publications

(270 citation statements)

References 13 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…Isogenic heterozygous Tmc1 Bth /+ mice maintained on a C3HeB/FeJ (C3H) background were obtained as a gift from Dr. Andrew Griffith 21 , and inbred with wild-type C3H mice obtained from Jackson Laboratory. Crossbred homozygous C3H- Tmc1 Bth/Bth were caged with C3H mice to generate heterozygous Tmc1 Bth /+ mice.…”

Section: Methodsmentioning

confidence: 99%

“…A dominant-negative missense mutation in TMC1 (p.M418K, c.T1253A) causes reduced single-channel current levels and calcium permeability 16 and progressive post-lingual sensorineural hearing loss in humans 18–20 . The Bth/+ mouse model carries the orthologous missense mutation (p.M412K, c.T1235A) in the mouse Tmc1 gene and exhibits progressive auditory response threshold elevation and progressive hair cell loss beginning at one month 21 . Since the orthologous mutations in human and mouse both cause progressive, profound hearing loss, the Bth/+ mouse is a promising model for the development of treatment strategies 21 .…”

mentioning

confidence: 99%

“…The Bth/+ mouse model carries the orthologous missense mutation (p.M412K, c.T1235A) in the mouse Tmc1 gene and exhibits progressive auditory response threshold elevation and progressive hair cell loss beginning at one month 21 . Since the orthologous mutations in human and mouse both cause progressive, profound hearing loss, the Bth/+ mouse is a promising model for the development of treatment strategies 21 .…”

mentioning

confidence: 99%

“…In Tmc1 Bth/+;Tmc2 +/+ mice (abbreviated as Bth/+ mice below), IHCs followed by the outer hair cells (OHCs) undergo progressive death 21 . To determine the effect of Cas9:Tmc1-mut3 sgRNA on Bth/+ hair cell survival, we injected Cas9:Tmc1-mut3:lipid complex into the scala media of P1 mice and harvested injected and uninjected cochleae after 8 weeks.…”

mentioning

confidence: 99%

“…To study the effect of Cas9:Tmc1-mut3:lipid injection on cochlear function in Bth/+ mice, we measured auditory brainstem responses (ABRs) that measure the sound-evoked neural output of the cochlea, as well as distortion product otoacoustic emissions (DPOAEs) that measure the amplification provided by OHCs 21 . In uninjected ears we observed profound attenuation of cochlear neural responses, with ABR thresholds ranging from 70-90 dB at 4 weeks (Fig.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

Gao

Tao

Lamas

et al. 2017

Nature

413

317

View full text Add to dashboard Cite

Although genetic factors contribute to almost half of all deafness cases, treatment options for genetic deafness are limited1–5. We developed a genome editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9:guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated in vitro and in primary fibroblasts genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like 1) Beethoven (Bth) mouse model, even though the mutant Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9:guide RNA:lipid complexes targeting the Bth allele into the cochlea of neonatal Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response (ABR) thresholds in injected ears compared with uninjected ears or ears injected with complexes that target an unrelated gene. Enhanced acoustic reflex responses were observed among injected compared to uninjected Bth/+ animals. These findings suggest protein:RNA complex delivery of target gene-disrupting agents in vivo as a potential strategy for the treatment of some autosomal dominant hearing loss diseases.

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

Gao

Tao

Lamas

et al. 2017

Nature

413

317

View full text Add to dashboard Cite

show abstract

Mouse mutagenesis and gene function

Kühn¹,

Wurst

2005

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

View full text Add to dashboard Cite

With the completion of the mouse and human genome sequences, a major challenge is the functional characterization of every gene within the mammalian genome. The mouse offers many advantages for the use of genetics to the study of human biology and disease. A variety of mouse mutagenesis technologies, either gene‐ or phenotype‐driven, are used as systematic approaches. The availability of the mouse genome supports gene‐driven approaches such as gene‐trap and targeted mutagenesis in embryonic stem (ES) cells, allowing an efficiency and precision of gene disruption unmatched among other mammals. Furthermore, chemical and transposon mutagenesis of the mouse genome allows to perform phenotype‐driven screens for the unbiased identification of phenotype–genotype correlations. These technologies already resulted in a collection of several thousand mutants. In this article on mouse mutagenesis and gene function, we present a comprehensive review of gene‐ and phenotype‐driven mouse mutagenesis strategies. Besides a summary of the basic principles of each approach, we emphasize on the latest and future developments of mouse mutagenesis.

show abstract