An ENU-Induced Mutation of Cdh23 Causes Congenital Hearing Loss, but No Vestibular Dysfunction, in Mice

Abstract

Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a Cdh23-null mutation and present with hearing loss and vestibular dysfunction. Two additional Cdh23 mouse mutants, salsa and erlong, each carry a homozygous Cdh23 missense mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea-induced c.7079T>A mutation in the Cdh23 gene. The mutation generates a missense change, p.V2360E, in Cdh23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The mutation affects a highly conserved Ca 2؉ -binding motif in extracellular domain 22, thought to be important for Cdh23 structure and dimerization. Molecular modeling suggests that the Cdh23 V2360E/V2360E mutation alters the structural conformation of the protein and affects Ca 2؉ -binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12. (Am J Pathol 2011, 179:903-914;

Cauli: A Mouse Strain with an Ift140 Mutation That Results in a Skeletal Ciliopathy Modelling Jeune Syndrome

“…E10.5 limb buds were dissected from wild-type, heterozygous and homozygous embryos, fixed and processed for scanning electron microscopy as previously described [72]. Tissues were viewed using a Philips XL30 FE scanning electron microscope.…”

Characterization of a novel ENU-generated myosin VI mutant mouse strain with congenital deafness and vestibular dysfunction

“…ENUmutagenesis programs have proven to be a highly valuable approach in identifying novel mutations and genes involved in the auditory pathway, as well as revealing novel functions of genes already known to be involved in hearing (Curtin et al, 2003;Hardisty et al, 2003;Hrabe de Angelis et al, 2000;Kiernan et al, 2001;Marcotti et al, 2006;Nolan et al, 2000;Rhodes et al, 2004Rhodes et al, , 2003Tsai et al, 2001;Vreugde et al, 2002). Initially, ENUmutagenesis programs focused on dominant disease-causing mutations, however, as the majority of human genetic deafness is recessively inherited, characterisation of recessive ENU-mutants, such as charlie, will be essential for gaining further insight into the development and functioning of the mammalian auditory system (Kermany et al, 2006;Manji et al, 2012Manji et al, , 2011a2011b;Parker et al, 2010). Given the high degree of similarity between the mouse and human inner ear, and the conserved role of Myo6 in the mammalian inner ear, charlie will be a valuable resource for gaining a more thorough understanding of the role Myo6 plays in hearing and balance, and may ultimately help to guide therapeutic approaches for patients with deafness attributable to Myo6 mutations.…”

Eeyore: A Novel Mouse Model of Hereditary Deafness

“…The cadherin family member, Cadherin 23 (Cdh23), is a major component of sensory hair cell tip links [24]–[26] and mutations in Cdh23 are responsible for the human deafness type DFNB12 [27] and Usher Syndrome Type 1D [27]–[29]. A number of analogous mouse models to these conditions have been reported [15], [30]–[35]. Several members of the phosphoinositide synthesis pathway have been reported in the literature to play an important role in hearing [36]–[39] and we recently identified a mouse model of progressive sensorineural hearing loss with a mutation in another member of this pathway, Synaptojanin 2 (Synj2) [11].…”

“…Cochleae from 12–14 week old mice were dissected, fixed and processed for SEM as previously described [15]. Tissues were viewed using a Philips XL30 FE scanning electron microscope.…”