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Johnson, K. R., Zheng, Q. Y., Weston, M. D., Ptacek, L. J. & Noben-Trauth, K. The Mass1frings mutation underlies early onset hearing impairment in BUB/BnJ mice, a model for the auditory pathology of Usher syndrome IIC. Genomics 85, 582-590

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Genomics (Impact Factor: 2.79). 06/2005; 85(5):582-90. DOI: 10.1016/j.ygeno.2005.02.006
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ABSTRACT The human ortholog of the gene responsible for audiogenic seizure susceptibility in Frings and BUB/BnJ mice (mouse gene symbol Mass1) recently was shown to underlie Usher syndrome type IIC (USH2C). Here we report that the Mass1frings mutation is responsible for the early onset hearing impairment of BUB/BnJ mice. We found highly significant linkage of Mass1 with ABR threshold variation among mice from two backcrosses involving BUB/BnJ mice with mice of strains CAST/EiJ and MOLD/RkJ. We also show an additive effect of the Cdh23 locus in modulating the progression of hearing loss in backcross mice. Together, these two loci account for more than 70% of the total ABR threshold variation among the backcross mice at all ages. The modifying effect of the strain-specific Cdh23ahl variant may account for the hearing and audiogenic seizure differences observed between Frings and BUB/BnJ mice, which share the Mass1frings mutation. During postnatal cochlear development in BUB/BnJ mice, stereocilia bundles develop abnormally and remain immature and splayed into adulthood, corresponding with the early onset hearing impairment associated with Mass1frings. Progressive base-apex hair cell degeneration occurs at older ages, corresponding with the age-related hearing loss associated with Cdh23ahl. The molecular basis and pathophysiology of hearing loss suggest BUB/BnJ and Frings mice as models to study cellular and molecular mechanisms underlying USH2C auditory pathology.

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    • "All four Vlgr1 mouse models are susceptible to audiogenic seizures (McMillan and White 2004; Skradski et al. 2001; Yagi et al. 2005). In all four Vlgr1 mouse models, the Usher syndrome symptoms are partially pheno-copied, especially the hearing loss phenotype (Johnson et al. 2005; McGee et al. 2006; Michalski et al. 2007; Yagi et al. 2007). A mild retinal defect was also reported in aged Vlgr1 knock-in mice (McGee et al. 2006). "
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    ABSTRACT: The very large G protein coupled receptor (Vlgr1) is a member of adhesion receptors or large N-terminal family B-7 transmembrane helixes (LNB7TM) receptors within the seven trans-membrane receptor superfamily. Vlgr1 is the largest GPCR identified to date; its mRNA spans 19 kb and encodes 6,300 amino acids. Vlgr1 is a core component of ankle-link complex in inner ear hair cells. Knock-out and mutation mouse models show that loss of Vlgr1 function leads to abnormal stereociliary development and hearing loss, indicating crucial roles of Vlgr1 in hearing transduction or auditory system development. Over the past 10 or so years, human genetics data suggested that Vlgr1 mutations cause Usher syndromes and seizures. Although significant progresses have been made, the details of Vlgr1's function in hair cells, its signaling cascade, and the mechanisms underlying causative effects of Vlgr1 mutations in human diseases remain elusive and ask for further investigation.
    Journal of Molecular Neuroscience 11/2012; 50(1). DOI:10.1007/s12031-012-9911-5 · 2.76 Impact Factor
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    • "BUB/BnJ and Frings inbred strains; Targeted kO Sound-induced seizures and progressive hearing loss Skradski et al., 2001; Zheng et al., 1999; Johnson et al., 2005 USH2A USH2A (Usher syndrome Type 2A) "
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    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2012; 295(11):1812-29. DOI:10.1002/ar.22579 · 1.53 Impact Factor
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    • "Stereocilia were disconnected and detached, the most severely affected bundles lost their polarity and graded height. At older ages, hair cells and spiral ganglion cells were degenerated [40]. "
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