Advantages of a Mouse Model for Human Hearing Impairment

Abstract

Hearing is a major factor in human quality of life. Mouse models are important tools for discovering the genes that are responsible for genetic hearing loss, and these models often allow the processes that regulate the onset of deafness in humans to be analyzed. Thus far, in the study of hearing and deafness, at least 400 mutants with hearing impairments have been identified in laboratory mouse populations. Analysis of through a combination of genetic, morphological, and physiological studies is revealing valuable insights into the ontogenesis, morphogenesis, and function of the mammalian ear. This review discusses the advantages of the mouse models of human hearing impairment and highlights the identification of the molecules required for stereocilia development in the inner ear hair cells by analysis of various mouse mutants.

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

“…Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).…”

Compound Heterozygosity of the Functionally Null <i>Cdh23^v-ngt</i> and Hypomorphic <i>Cdh23^ahl</i> Alleles Leads to Early-onset Progressive Hearing Loss in Mice

“…However, the study of Holme and Steel did not confirm that the expression of early-onset progressive hearing loss is associated with a compound heterozygous state comprised of a functionally null allele and a hypomorphic allele because the authors analyzed Cdh23 v heterozygous mice on mixed genetic backgrounds that were 50% CBA/Ca and 50% BS, with some BALB/c [11], and inbred mice are known to have several other AHL susceptibility loci [15, 25]. In our study, to avoid effects from modifier genes on other chromosomes, we produced congenic mice by crossing the Cdh23 v-ngt null allele with the hypomorphic Cdh23 ahl allele onto the C57BL/6J background.…”

“…ICR- Cdh23 v-ngt/v-ngt homozygous mutants were obtained from Niigata University (Niigata, Japan) and were then crossed with C57BL/6J mice (Clea Japan, Tokyo, Japan) that had a Cdh23 ahl allele [15, 26]. The F 1 Cdh23 v-ngt/ahl compound heterozygous mice were backcrossed with C57BL/6J mice for 20 generations at the Tokyo Metropolitan Institute of Medical Science (Tokyo, Japan), and the Cdh23 v-ngt/ahl compound heterozygote and Cdh23 v-ngt/v-ngt homozygote offspring of breeder pairs consisting of a Cdh23 v-ngt/ahl female and a Cdh23 v-ngt/v-ngt male were used for all of the experiments.…”

“…For studies of human genetic deafness, inbred mouse strains are excellent animal models because the mouse auditory system is anatomically similar to that of humans [2, 33]. As found in humans, inbred strains also differ in their predisposition to age-related hearing loss (AHL) [15, 25]. One AHL susceptibility gene, ahl , is located on chromosome 10 [12], and ahl possesses a functional SNP (G753A) in the coding sequence of cadherin 23 ( Cdh23 ) that creates a splice junction leading to the expression of a transcript lacking exon 7 [26].…”

“…The susceptible allele is shared by approximately 80% of inbred strains with AHL such as the C57BL/6J strain [26]. The C57BL/6J strain with homozygosity of the Cdh23 ahl allele expresses only exon 7-lacking CDH23 and exhibits late-onset AHL, i.e., severe hearing loss at 9–12 months of age [9, 15, 21, 36]. Conversely, inbred strains transmitting the Cdh23 753G resistant allele mostly maintain life-long hearing, as exemplified in C3H/HeN mice [15].…”