Compound heterozygosity of the functionally null Cdh23(v-ngt) and hypomorphic Cdh23(ahl) alleles leads to early-onset progressive hearing loss in mice.
Yuki Miyasaka,Sari Suzuki,Sari Suzuki,Yasuhiro Ohshiba,Yasuhiro Ohshiba,Kei Watanabe,Kei Watanabe,Yoshihiko Sagara,Shumpei P. Yasuda,Kunie Matsuoka,Hiroshi Shitara,Hiromichi Yonekawa,Ryo Kominami,Yoshiaki Kikkawa +13 more
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TLDR
Findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process, and hypothesize that the reduction of Cdh23 gene dosage in Cdh 23v-ngt/ahl mice leads to the degeneration of stereocilia, which consequently reduces tip link tension.Abstract:
The waltzer (v) mouse mutant harbors a mutation in Cadherin 23 (Cdh23) and is a model for Usher syndrome type 1D, which is characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of progressive retinitis pigmentosa. In mice, functionally null Cdh23 mutations affect stereociliary morphogenesis and the polarity of both cochlear and vestibular hair cells. In contrast, the murine Cdh23(ahl) allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to age-related hearing loss in many inbred strains. We produced congenic mice by crossing mice carrying the v niigata (Cdh23(v-ngt)) null allele with mice carrying the hypomorphic Cdh23(ahl) allele on the C57BL/6J background, and we then analyzed the animals' balance and hearing phenotypes. Although the Cdh23(v-ngt/ahl) compound heterozygous mice exhibited normal vestibular function, their hearing ability was abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and rapid age-dependent elevation of ABR thresholds compared with Cdh23(ahl/ahl) homozygous mice. We found that the stereocilia developed normally but were progressively disrupted in Cdh23(v-ngt/ahl) mice. In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate the mechanoelectrical transduction channels in hair cells. We hypothesize that the reduction of Cdh23 gene dosage in Cdh23(v-ngt/ahl) mice leads to the degeneration of stereocilia, which consequently reduces tip link tension. These findings indicate that CDH23 plays an important role in the maintenance of tip links during the aging process.read more
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Journal ArticleDOI
Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities.
Pranav Dinesh Mathur,Jun Yang +1 more
TL;DR: This review focuses on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH.
Journal ArticleDOI
Photoreceptor Cilia and Retinal Ciliopathies.
TL;DR: The structure and composition of PSC and different forms of ciliopathies with retinal involvement are described and the genetics of the IRDs are reviewed, which are monogenic disorders but genetically diverse with regard to causality.
Journal ArticleDOI
Stereocilia morphogenesis and maintenance through regulation of actin stability
TL;DR: In this article, the authors describe stereocilia actin regulation in the context of an emerging "tip turnover" model where actin assembles and disassembles at the outer layers while the remainder of the core is exceptionally stable.
Stereocilia morphogenesis and maintenance through regulation of actin stability
TL;DR: This review aims to describe stereocilia actin regulation in the context of an emerging "tip turnover" model where actin assembles and disassembles at stereOCilia tips while the remainder of the core is exceptionally stable.
Journal ArticleDOI
Distinct expression and function of whirlin isoforms in the inner ear and retina: an insight into pathogenesis of USH2D and DFNB31
Pranav Dinesh Mathur,Junhuang Zou,Tihua Zheng,Ali Almishaal,Yong Wang,Qian Chen,Le Wang,Deepti Vashist,Steve D.M. Brown,Albert H. Park,Jun Yang +10 more
TL;DR: Investigating theDFNB31 gene found that the mouse DFNB31 ortholog expressed different mRNA variants and whirlin protein isoforms in the cochlea and retina, where these isoforms played different roles spatially and temporally.
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Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells.
Piotr Kazmierczak,Hirofumi Sakaguchi,Joshua Tokita,Elizabeth M. Wilson-Kubalek,Ronald A. Milligan,Ulrich Müller,Bechara Kachar +6 more
TL;DR: The studies define the molecular composition of tip links and provide a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.
Journal ArticleDOI
Usher Syndrome 1D and Nonsyndromic Autosomal Recessive Deafness DFNB12 Are Caused by Allelic Mutations of the Novel Cadherin-Like Gene CDH23
Julie M. Bork,Linda M. Peters,Saima Riazuddin,Saima Riazuddin,S. L. Bernstein,Zubair M. Ahmed,Zubair M. Ahmed,Seth L. Ness,Robert C. Polomeno,Arabandi Ramesh,Arabandi Ramesh,Melvin D. Schloss,C. R. Srikumari Srisailpathy,C. R. Srikumari Srisailpathy,Sigrid Wayne,Susan Bellman,Dilip Desmukh,Zahoor Ahmed,Shaheen N. Khan,Vazken M. Der Kaloustian,X. Cindy Li,Anil K. Lalwani,Sheikh Riazuddin,Maria Bitner-Glindzicz,Walter E. Nance,Xue-Zhong Liu,Graeme Wistow,Richard J.H. Smith,Andrew J. Griffith,Edward R. Wilcox,Thomas B. Friedman,Robert J. Morell +31 more
TL;DR: Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22, but mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in Families with USH1D.
Journal ArticleDOI
The mosaic structure of variation in the laboratory mouse genome
Claire M. Wade,Claire M. Wade,Edward J. Kulbokas,Andrew Kirby,Michael C. Zody,James C. Mullikin,Eric S. Lander,Kerstin Lindblad-Toh,Mark J. Daly +8 more
TL;DR: An analysis of the fine structure of variation in the mouse genome, using single nucleotide polymorphisms (SNPs), suggests that the genomes of these inbred strains are mosaics with the vast majority of segments derived from domesticus and musculus sources.
Journal ArticleDOI
Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D
Hanno J. Bolz,von Brederlow B,Alfredo Ramirez,Elizabeth C. Bryda,Kerstin Kutsche,Hans Gerd Nothwang,Mathias W. Seeliger,del C-Salcedó Cabrera M,Vila Mc,Molina Op,Andreas Gal,Christian Kubisch +11 more
TL;DR: The data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype, and it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.