부산대학교 도서관

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 waltzermouse strains each harbor a Cdh23-null mutation and present with hearing loss and vestibular dysfunction. Two additional Cdh23mouse mutants, salsaand erlong, each carry a homozygous Cdh23missense 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.7079TA mutation in the Cdh23gene. 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 Ca2+-binding motif in extracellular domain 22, thought to be important for Cdh23structure and dimerization. Molecular modeling suggests that the Cdh23V2360E/V2360Emutation alters the structural conformation of the protein and affects Ca2+-binding properties. Similar to salsamice, but in contrast to waltzermice, hair bundle development is normal in jeraand hearing loss appears to be due to the loss of tip links. Thus, jerais a novel mouse model for DFNB12.