title: 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.
authors.affiliation: Genetic Hearing Research Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia. shehnaaz.manji@mcri.edu.au
authors.forename: Shehnaaz S M
authors.initials: SS
authors.lastname: Manji
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Miller
authors.forename: Louise H
authors.initials: LH
authors.lastname: Williams
authors.forename: Lotte
authors.initials: L
authors.lastname: Andreasen
authors.forename: Maria
authors.initials: M
authors.lastname: Siboe
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rose
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Michael
authors.initials: M
authors.lastname: Kuiper
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D005038:Ethylnitrosourea / Q000494:pharmacology; D006309:Hearing; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015837:Vestibular Diseases / Q000235:genetics / Q000473:pathology*; D014722:Vestibule, Labyrinth / Q000473:pathology
chemical_list: D015820:Cadherins; C499091:Cdh23 protein, mouse; D005038:Ethylnitrosourea