Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses
Introduction
Genetic impairment of hearing affects about one of every 2000 children (Morton, 1991). About 70% of all genetic forms of human deafness appear to be non-syndromic and about 80% of those are expressed as recessive genes. Genes responsible for on-yndromic earing mpairment (NSHI) are difficult to identify because of their extreme genetic heterogeneity and absence of clinical criteria allowing for their differentiation (Petit, 1996). During the last decade, analyses of NSHI among small, isolated populations, together with current genetic mapping techniques, have resulted in the identification of more than 45 genetically distinct forms of NSHI; however, only eight underlying genes have been cloned (Van Camp and Smith, 1998).
The mouse is an excellent animal model for the study of human genetic deafness (Steel and Brown, 1996). The mouse cochlea is anatomically similar to that of humans (Steel and Bock, 1983), and hereditary abnormalities of the inner ear have been shown to be similar in both humans and mice (Brown and Steel, 1994). Most importantly, the homologies between the mouse and human genomes are well established. Defined regions of chromosomes are highly conserved for gene content and gene linkages between these two mammalian species. There are nearly 100 naturally occurring mouse mutations with hearing impairment that may serve as models for human deafness (Lyon et al., 1996; Steel, 1995). Genetic crosses of mice can produce thousands of progeny for mapping and positionally cloning spontaneous mutations. Genetically engineered mice with targeted gene disruptions can be used to examine and validate genes that may be candidates for any of the human deafness genes.
The genetic analysis of mouse deafness mutations already has proven instrumental in the identification of four human NSHI genes. Mice homozygous for the shaker-1 mutation (sh1) are characterized by hyperactivity, head-shaking and circling behaviors and also are deaf due to a neuroepithelial defect in the cochlea. sh1 was shown by positional cloning to be a mutation of the Myo7a gene, which encodes an unconventional myosin-type protein (Gibson et al., 1995). Subsequently, the homologous MYO7A gene in humans was shown to be responsible for both dominant (DFNA11) and recessive (DFNB2) forms of NSHI (Liu et al., 1997a, Liu et al., 1997b), as well as for Usher syndrome type 1B (Weil et al., 1995). Mice homozygous for the shaker-2 mutation (sh2) have the same phenotype as sh1 mice. sh2 recently was shown to be a mutation of the Myo15 gene (Probst et al., 1998) which encodes another unconventional myosin-type protein. Concurrently, the homologous MYO15 gene in humans was shown to be responsible for a recessive form of NSHI, DFNB3 (Wang et al., 1998). A targeted inactivation of the Pou4f3 gene in the mouse causes severe deafness (Erkman et al., 1996). 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 (Vahava et al., 1998). Additional mouse hearing-related genes will likely be found that help to identify genes for other forms of human deafness.
The deafness caused by most mouse mutations is congenital and usually associated with other phenotypic effects. To our knowledge, only two mouse mutations, deafness (dn) (Keats et al., 1995) and deaf (νdf) (Deol, 1956), have been reported that are not associated with balance or with other non-auditory defects. In contrast to the congenital, syndromic deafness caused by most mouse mutations, certain inbred strains of mice exhibit a progressive, non-syndromic hearing loss, with onset at more advanced ages. These strains have provided useful models for human age-related hearing loss (AHL), or presbycusis. Several inbred strains of mice have been shown to exhibit differing severity and onset of AHL (Henry, 1982; Willott, 1983). The genetic nature of AHL in the few inbred strains examined so far has been attributed to 1–3 major genes per strain (Erway et al., 1993); one of these genes has been mapped to chromosome 10 (Johnson et al., 1997). The combined effects of multiple AHL genes may contribute to the earlier onset and greater severity of hearing impairment observed in some strains. It is not known how many different AHL genes are present collectively in existing mouse strains. Some of the genes contributing to AHL may also exacerbate the effects of single gene mutations causing hearing impairment, as may be the case for a strain-specific modifier (mdfw) of the deaf waddler mutations (Noben-Trauth et al., 1997).
To begin to identify genes that contribute to hearing loss in both inbred and mutant strains of mice, a large-scale, auditory screening project has been undertaken at The Jackson Laboratory (TJL). This project, supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD), was specifically designed to provide genetic models for non-syndromic forms of human deafness. More than three million mice are produced annually at TJL. These mice belong to nearly 1700 distinct inbred strains, including standard inbred strains, recombinant inbred strains, congenic inbred strains, and inbred strains carrying both spontaneous and induced mutations. Most of these inbred strains have not been tested for hearing ability prior to this screening effort.
Here, we report auditory brainstem response (ABR) thresholds for 80 inbred strains of mice and discuss the implications of these measurements in terms of establishing a reference for hearing ability of commonly used inbred strains of mice, identifying strains with significant hearing impairment, and defining the characteristic attributes of the impairment observed in these strains. This is the first publication resulting from this screening program, including results for 61 inbred strains of mice with normal hearing and 19 inbred strains or substrains with hearing impairment before 3 months of age. Genetic crosses are in progress to determine inheritance patterns for the hearing loss observed in some of these inbred strains and to map the responsible genes.
Section snippets
Mice and animal care
All mice used in this study were produced within the production or research facilities of TJL. Prior to electrode placement, animals were anesthetized by intraperitoneal injection with Avertin (tribromoethanol stabilized in tertiary amyl hydrate) given at a dose of 5 mg tribromoethanol/10 g body weight. Body temperature was maintained at 37–38°C by placing anesthetized mice on an isothermal pad (Deltaphase, model 39dp, Braintree Scientific Inc., Massachusetts). The care and use of the animals
Inbred strains of mice with normal ABR thresholds
As a reference for normal hearing, we repeatedly tested CBA/CaJ mice at four ages from 9 to 39 weeks (Fig. 1, Table 1). The mean thresholds for CBA/CaJ mice were 36, 24, 15, and 39 dB SPL for the click, 8 kHz, 16 kHz, and 32 kHz stimuli, respectively. We then defined as hearing impaired those inbred strains that exhibited average ABR thresholds at least 15 dB SPL above these mean values, for any of the four acoustic stimuli at any age of testing. An increase of 15 dB is at least three standard
Appropriateness of ABR for assessing hearing sensitivity
Hearing is defined as a perception and, as such, behavioral measures would be most appropriate. However, behavioral thresholds can be confounded by a great many processes, any of which could be aberrant (Henry, 1982). The ABR is an evoked potential measure of auditory activity in the brainstem that is commonly used for prediction of hearing levels in animals and young children. ABRs include several waves; the first wave represents cochlear and auditory nerve activity and the late waves reflect
Acknowledgements
We thank Dr. Ed Leiter, The Jackson Laboratory (TJL), for the ALR, ALS, and NOD-related mice and information about them. We also thank Drs. P. Nishina and V. Letts, TJL, for their careful review of the manuscript. This work was supported by the National Institutes of Health Contract N01 DC62108 from NIDCD and Core Grant CA34196 from NCI. Preliminary findings were presented at the 20th and 21st meetings of the Association for Research in Otolaryngology, St. Petersburg Beach, FL, 1997 and 1998.
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