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

University of California, San Francisco, San Francisco, California, United States
Genomics (Impact Factor: 2.28). 06/2005; 85(5):582-90. DOI: 10.1016/j.ygeno.2005.02.006
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2012 · Journal of Molecular Neuroscience
  • Source
    • "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) "
    [Show abstract] [Hide abstract]
    ABSTRACT: This article is a review of the genes and genetic disorders that affect hearing in humans and a few selected mouse models of deafness. Genetics is playing an increasingly critical role in the practice of medicine. This is not only in part to the importance that genetic knowledge has on traditional genetic diseases but also in part to the fact that genetic knowledge provides an understanding of the fundamental biological process of most diseases. The proteins coded by the genes related to hearing loss (HL) are involved in many functions in the ear, such as cochlear fluid homeostasis, ionic channels, stereocilia morphology and function, synaptic transmission, gene regulation, and others. Mouse models play a crucial role in understanding of the pathogenesis associated with these genes. Different types of familial HL have been recognized for years; however, in the last two decades, there has been tremendous progress in the discovery of gene mutations that cause deafness. Most of the cases of genetic deafness recognized today are monogenic disorders that can be broadly classified by the mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance) and by the presence of associated phenotypic features (i.e., syndromic; and nonsyndromic). In terms of nonsyndromic HL, the chromosomal locations are currently known for ∼ 125 loci (54 for dominant and 71 for recessive deafness), 64 genes have been identified (24 for dominant and 40 for recessive deafness), and there are many more loci for syndromic deafness and X-linked and mitochondrial DNA disorders ( Thus, today's clinician must understand the science of medical genetics as this knowledge can lead to more effective disease diagnosis, counseling, treatment, and prevention. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
    Preview · Article · Nov 2012 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sensorineural hearing loss is one of the most common disabilities in humans. It is estimated that about 278 million people worldwide have slight to extreme hearing loss in both ears, which results in an economic loss for the country and personal loss for the individual. It is thus critical to have a deeper understanding of the causes for hearing loss to better manage and treat the affected individuals. The mouse serves as an excellent model to study and recapitulate some of these phenotypes, identify new genes which cause deafness, and to study their roles in vivo and in detail. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. The development and morphogenesis of the inner ear from an ectodermal layer into distinct auditory and vestibular components depends on well-coordinated gene expression and well-orchestrated signaling cascades within the otic vesicle and interactions with surrounding layers of tissues. Any disruption in these pathways can lead to hearing impairment. This review takes a look at some of the genes and their corresponding mice mutants that have shed light on the mechanism governing hearing impairment (HI) in humans.
    Full-text · Article · Oct 2011
Show more