Mouse models to study inner ear development and hereditary hearing loss

Friedman, Lilach M.; Dror, Amiel A.; Avraham, Karen B.

doi:10.1387/ijdb.072365lf

Cited by 105 publications

(88 citation statements)

References 247 publications

(207 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several genes essential for hearing in humans were identified after they had already been demonstrated to be associated with deafness in mice. 8 Using homozygosity mapping and candidate gene analysis, we identified a homozygous nonsense mutation in CLIC5 in a consanguineous Turkish family (W05-009). The orthologous mouse gene, Clic5, was described to be mutated in the jitterbug (jbg) mouse exhibiting congenital progressive hearing impairment and vestibular dysfunction due to progressive hair cell degeneration.…”

Section: Introductionmentioning

confidence: 99%

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

et al. 2014

View full text Add to dashboard Cite

In a consanguineous Turkish family diagnosed with autosomal recessive nonsyndromic hearing impairment (arNSHI), a homozygous region of 47.4 Mb was shared by the two affected siblings on chromosome 6p21.1-q15. This region contains 247 genes including the known deafness gene MYO6. No pathogenic variants were found in MYO6, neither with sequence analysis of the coding region and splice sites nor with mRNA analysis. Subsequent candidate gene evaluation revealed CLIC5 as an excellent candidate gene. The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction. Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T4A (p. (Cys32Ter)) that segregated with the hearing loss. Further analysis of CLIC5 in 213 arNSHI patients from mostly Dutch and Spanish origin did not reveal any additional pathogenic variants. CLIC5 mutations are thus not a common cause of arNSHI in these populations. The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade. Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction. Although we demonstrate that CLIC5 is expressed in many other human tissues, no additional symptoms were observed in these patients. In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin.

show abstract

Section: Introductionmentioning

confidence: 99%

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Auditory mouse mutants have contributed to the identification of candidate deafness-causing genes in humans [6,10,11]. Due to the remarkable structural similarity between human and mouse auditory systems, auditory mouse mutants have provided valuable insight into the ontogenesis, morphogenesis and function of the human ear [3].…”

Section: Introductionmentioning

confidence: 99%

“…Vertebrate inner ear hair cells are mechanosensors that transduce mechanical forces arising from sound waves and head movement providing the sense of hearing and balance, respectively [13,23]. Stereocilia is a mechanically sensitive organelle, which consists of actin filaments, nonmuscle-type myosin and several scaffold proteins [6,10,11]. Mouse mutations underlying vestibular dysfunction and deafness occur preferentially in genes encoding such proteins.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and Expression Analysis of a Novel Spontaneous Myosin VI Null Mutant Mouse

et al. 2010

View full text Add to dashboard Cite

Abstract:In humans, hearing is a major factor in quality of life. Mouse models are important tools for the discovery of genes responsible for genetic hearing loss, often enabling analysis of the processes that regulate the onset of deafness in humans. Thus far, at least 400 deafness mutants have been discovered in laboratory mouse populations and used in the study of deafness. Here we report the discovery of a new spontaneous recessive Rinshoken shaker/waltzer (rsv) mutant derived from our in-house C57BL/6J stock, which exhibits circling and/or head-tossing behaviour and complete lack of auditory brain response to any sound pressure. The hearing and balance phenotypes are associated with structural defects, in particular, disorganisation and fusion of stereocilia in the inner ear hair cells. Two sets of intersubspecific N 2 mice were generated for the positional cloning of the rsv mutation. The mutant locus was mapped to a 4.8-Mb region of chromosome 9, which contains myosin VI (Myo6), a gene responsible for deafness in humans and Snell's waltzer mutation in mice. The rsv mutant showed reduced expressions of Myo6 mRNA and MYO6 protein in the inner ear. Moreover, no immunoreactivity was observed in the cochlear and vestibular hair cells in the rsv mutant mice. We sequenced the genomic region (30,154 bp) of Myo6, including all coding exons, a non-coding exon, UTRs and the Myo6 promoter; however, no mutation was discovered in these regions. We therefore speculate that loss of MYO6 expression might cause shaker/waltzer behaviour and deafness in the rsv mutant; also, loss of MYO6 expression might be the result of mutations in an unidentified regulatory region(s) of the gene.

show abstract

“…The molecular mechanisms governing the ankle link and the basal link assemblies are not well characterized, but there is evidence showing several USH gene products including cadherin 23, VlgR, and Usherin are crucial for their formation (8)(9)(10). Studies using the animal models of USH showed that mutation of any one of the Usher genes affects the development of stereocilia at different degrees (11)(12)(13)(14).…”

mentioning

confidence: 99%

Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23

Pan

Yan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

The hereditary hearing-vision loss disease Usher syndrome (USH) is caused by defects in several proteins, most of which form an integrated protein network called Usher interactome. Harmonin/ Ush1C is a master scaffold in the assembly of the Usher protein complexes, because harmonin is known to bind to every protein in the Usher interactome. However, the biochemical and structural mechanism governing the Usher protein complex formation is largely unclear. Here, we report that the highly-conserved Nterminal fragment of harmonin (N-domain) immediately preceding its PDZ1 adopts an autonomously-folded domain. We discovered that the N-domain specifically binds to a short internal peptide fragment of the cadherin 23 cytoplasmic domain. The structures of the harmonin N-domain alone and in complex with the cadherin 23 internal peptide fragment uncovered the detailed binding mechanism of this interaction between harmonin and cadherin 23. We further elucidated the harmonin PDZ domain-mediated cadherin 23 binding by solving the structure of the second harmonin PDZ domain in complex with the cadherin 23 carboxyl tail. The multidentate binding mode between harmonin and cadherin 23 provides a structural and biochemical basis for the harmonin-mediated assembly of stable tip link complex in the auditory hair cells.PDZ domains ͉ scaffold protein ͉ Usher syndrome

show abstract

Mouse models to study inner ear development and hereditary hearing loss

Cited by 105 publications

References 247 publications

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

Phenotypic and Expression Analysis of a Novel Spontaneous Myosin VI Null Mutant Mouse

Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23

Contact Info

Product

Resources

About