Mutations in Grxcr1 Are The Basis for Inner Ear Dysfunction in the Pirouette Mouse

Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2010; 86(2):148-60. DOI: 10.1016/j.ajhg.2010.01.016
Source: PubMed


Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells.

Download full-text


Available from: Nicholas D Allen
  • Source
    • "The absence of GRXCR1 results in formation of relatively short and thin stereocilia and cytocauds indicating actin abnormalities. This suggests that GRXCR1 plays an active role in development of actin architecture in the stereocilia (Beyer et al., 2000; Odeh et al., 2010). "

    Full-text · Chapter · Mar 2012
  • Source
    • "In the spontaneous Espn mouse mutant, jerker, a missense mutation reduces levels of espin in homozygous mice resulting in abnormally short and thin stereocilia despite the presence of espin-like protein encoded by Espnl, and several other actin cross-linkers in these structures (Sekerkova et al., 2006, 2011). The spontaneous Grxcr1 mouse mutant, pirouette, also produces abnormally thin stereocilia, though the molecular mechanisms remain to be investigated (Odeh et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary deafness is genetically heterogeneous such that mutations of many different genes can cause hearing loss. This review focuses on the evidence and implications that several of these deafness genes encode actin-interacting proteins or actin itself. There is a growing appreciation of the contribution of the actin interactome in stereocilia development, maintenance, mechanotransduction and malfunction of the auditory system.
    Full-text · Article · Dec 2011 · Hearing research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The RHIC requires an extensive Access Control System to protect personnel from radiation, oxygen deficiency and electrical hazards. In addition, the complicated nature of operation of the collider as part of a complex of other accelerators necessitates the use of active electronic measurement circuitry to ensure compliance with established operational safety limits. Solutions were devised which permit the use of modern computer and interconnection technology for safety-critical applications, while preserving and enhancing, tried and proven protection methods. In addition a set of Guidelines, regarding required performance for accelerator safety systems and a handbook of design criteria and rules were developed to assist future system designers and to provide a framework for internal review and regulation. This paper is offered in the hope and belief that many of the techniques developed as part of the Access and Operational Safety systems designed for RHIC (and other recently completed large research accelerators) may be directly applicable to smaller research and clinical treatment facilities. Because of the relatively short length of this paper, I will concentrate on four topics: novel features of our system design; potentially useful applications of probability theory empowered by these system concepts: a listing of configuration control and design approaches, which when followed, will enable one to design high reliability hardware and systems (to meet required functionality); software design concepts and approaches
    Preview · Conference Paper · Jan 1994
Show more