Background - Mutations with Hearing Impairment
The mouse as a model for human hearing impairment - Hearing impairment is the most common sensory deficit in human populations and has a strong genetic component; it affects about one of every 1,000 children, and at least half of these cases are hereditary [156]. The mouse is an excellent animal model for the study of human genetic deafness because the anatomy, function, and hereditary abnormalities of the inner ear are similar in both humans and mice [157, 158]. The genetic analysis of mouse mutations has already helped to identify several human deafness genes. The mouse shaker-1 mutation (sh1) was shown by positional cloning to be a mutation of the Myo7a gene, which encodes an unconventional myosin-type protein [159]. Subsequently, the homologous MYO7A gene in humans was shown to be responsible for both dominant (DFNA11) and recessive (DFNB2) forms of non-syndromic deafness [160, 161] as well as for Usher syndrome type1B [162]. The mouse shaker-2 mutation (sh2) was shown to be a mutation of the Myo15 gene [163], which encodes another unconventional myosin-type protein. The homologous MYO15 gene in humans was shown to be responsible for a recessive form of non-syndromic deafness, DFNB3 [164]. A targeted inactivation of the Pou4f3 gene in the mouse causes severe deafness [165]. The chromosomal localization of the homologous human POU4F3 gene near a dominant form of NSHI (DFNA15) ultimately led to its identification as the responsible gene [166].
Need for more non-syndromic hearing models - Because of the extreme genetic heterogeneity of hearing loss in human populations and the absence of clinical criteria allowing for their differentiation, many genes underlying both syndromic and non-syndromic forms of deafness remain to be identified [167]. More than 60 genetically distinct forms of non-syndromic deafness have been identified in humans during the last decade and many more remain to be discovered; only 13 of the estimated hundreds of genes affecting hearing have been cloned [168]. Identification of additional mouse mutations will help identify many of the unknown genes causing deafness in both humans and mice. Most genetic forms of human deafness appear to be non-syndromic. However, there is a lack of non-syndromic mutations in mice; the deafness caused by most mouse mutations is usually associated with other phenotypic effects such as abnormal behavior or lack of pigmentation, and animal caretakers would not otherwise notice hearing-impaired mice. To our knowledge, only two reported mouse mutations, deafness (dn) [169] and the extinct vdf mutation [170], are not associated with other defects. Inducing a high frequency of mutations by chemical mutagenesis makes it feasible to efficiently screen mice for inherited forms of non-syndromic hearing impairment. Because most forms of inherited deafness are recessive in humans, our recessive scheme in mice will improve the likelihood of identifying homologous genes.
