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Genetics, Vol. 173, 2111-2119, August 2006, Copyright © 2006
doi:10.1534/genetics.106.057372
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,3
* Section on Gene Structure and Function and Hearing Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850-3320, Department of Otolaryngology, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan and GSF Research Center for Environment and Health, Institute of Experimental Genetics, Neuherberg 85764, Germany
3 Corresponding author: National Institutes of Health, 5 Research Court, Rockville, MD 20850-3320.
E-mail: griffita{at}nidcd.nih.gov
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Dominant and recessive mutations of transmembrane channel-like gene 1 (TMC1) cause nonsyndromic SNHL at the DFNA36 and DFNB7/B11 loci, respectively (KURIMA et al. 2002, 2003). TMC1 encodes a polytopic transmembrane protein of unknown function that is expressed in cochlear hair cells (KURIMA et al. 2002; VREUGDE et al. 2002). In mice, dominant and recessive mutations of Tmc1 cause SNHL in the Beethoven (Bth) and deafness (dn) mouse lines, respectively (KURIMA et al. 2002; VREUGDE et al. 2002). Whereas DFNB7/B11 and dn homozygotes have severe to profound congenital hearing loss, heterozygous carriers of Bth and DFNA36 mutations have delayed-onset, progressive SNHL. SNHL in Beethoven and deafness mice is associated with rapid degeneration of cochlear hair cells (BOCK and STEEL 1983; VREUGDE et al. 2002), indicating that Tmc1 is required for normal hair cell function or survival.
The mammalian cochlea contains two types of hair cells distinguished by their location, morphology, and function (FROLENKOV et al. 2004). In general terms, inner hair cells (IHCs) have primarily afferent innervation and function as sensory cells transducing and transmitting auditory signals to the central nervous system. Outer hair cells (OHCs) receive principally efferent innervation and have a distinctive electromotile property postulated to underlie active biomechanical amplification of auditory stimuli. As a result of this active amplification, OHCs generate sounds known as otoacoustic emissions (OAEs) that can be measured noninvasively in living humans and mice with a sensitive microphone in the external auditory canal. In contrast, evaluation of hearing levels by auditory brainstem response (ABR) threshold analysis is an overall measure of peripheral auditory function, including both inner and outer hair cell function. Primary damage or secondary degeneration of OHCs characterizes many common hearing loss phenotypes, such as presbycusis, in humans. Since genetic modifiers are excellent candidates for etiologic determinants of these complex traits (FRIEDMAN et al. 2000; SCHULTZ et al. 2005), including presbycusis, we sought to identify modifiers of hair cell degeneration in Beethoven mice.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Tmc1 genotype analysis:
Genomic DNA was prepared from tail clip biopsies by a phenol/chloroform extraction procedure. A 213-bp fragment of Tmc1 exon 13 was amplified with forward (5'-TAT TAA AGGGAC CGC TCT GAA AAC-3') and reverse (5'-ATC CAT CAA GGC GAG AAT GAA TAC-3') primers in a 20-µl volume containing 50 ng DNA, 20 pmol of each primer, 200 µmol/liter of each dNTP, 1.5 mmol/liter MgCl2, and 1.6 units Taq DNA polymerase. Amplification conditions comprised an initial 2-min denaturation at 95°, followed by 30 step-cycles of 30 sec at 95°, 30 sec at 57°, and 45 sec at 72°, with a final elongation of 5 min at 72°. PCR products were directly sequenced on an automated sequencer (ABI-PRISM, model 3700; Applied Biosystems, Foster City, CA).
ABR and distortion product otoacoustic emissions analyses:
ABR thresholds were measured as described (SZYMKO-BENNETT et al. 2003) with some modifications: we used alternating polarity click and tone-burst stimuli of 47-µsec and 5-msec duration, respectively. The number of stimulus presentations was varied from 128 to 1024 depending on signal-to-noise ratio, and suprathreshold stimulus intensities were initially decreased in 10-dB steps followed by 5-dB steps at lower intensities to determine the response threshold. When no waveform was detectable at the highest stimulus level of 90 dB sound pressure level (SPL), the threshold was considered to be 95 dB SPL for subsequent analyses.
Distortion product otoacoustic emissions (DPOAEs) were recorded with an acoustic probe (ER-10C; Etymotic Research, Elk Grove Village, IL) using DP2000 DPOAE measurement system version 3.0 (Starkey Laboratory, Eden Prairie, MN). Two primary tones with frequency ratio f2/f1 = 1.2 were presented at intensity levels L1 = 65 dB SPL and L2 = 55 dB SPL. f2 was varied in one-sixth-octave steps from 
4 to 16 kHz. DP-grams comprised 2f1-f2 DPOAE amplitudes as a function of f2. Due to the limited frequency response of the acoustical transducers of the ER-10C probe, the software was able to correct stimulus intensities only at frequencies <16 kHz. Therefore, reliable DPOAE measurements were possible only at f2 frequencies <16 kHz. Table 1 shows the numbers of mice tested by ABR and DPOAE analyses.
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80 hair cell positions/row with an intact, degenerated, or lost hair cell. Hair cells were counted in at least six mutant or four control ears for each genotype and developmental time point and were considered to be degenerated if the cell soma or stereocilia were absent. Table 2 shows the numbers of mice examined histologically.
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20-cM intervals. The Jackson Laboratory Mouse Genome Informatics website (http://www.informatics.jax.org/) was the source of genetic map positions of STR markers. We analyzed additional markers (listed in Table 4) at loci with significant or suggestive linkage. PCR amplification conditions comprised an initial denaturation step of 95° for 2 min, 33 step-cycles of 95° for 30 sec, 51–60° for 30 sec, and 72° for 45 sec, followed by a final elongation at 72° for 5 min. Amplification products were separated by 3% agarose (NuSieve 3:1; Cambrex Bio Science Rockland, Rockland, ME) gel electrophoresis and visualized by ethidium bromide staining and ultraviolet illumination.
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40% of the total duct distance from the apex (VIBERG and CANLON 2004). The average of the six DPOAE values was analyzed for association with STR marker genotypes on a Macintosh computer with QTX software downloaded from http://www.mapmanager.org/mmQTX.html (MANLY et al. 2001). The significance threshold of likelihood ratio statistic (LRS) = 12.4 for interval mapping was estimated by the Quick Test application of QTX (MANLY et al. 2001). Conventional base-10 LOD scores were calculated by dividing the LRS by 4.61 (MANLY et al. 2001).
Statistical analysis:
The significance of differences in ABR thresholds and DPOAE amplitudes was calculated by Mann–Whitney U testing with Stat View version 4.51 software (Abacus Concepts, Berkeley, CA) on a Macintosh computer.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Cochlear hair cell degeneration:
We evaluated IHC and OHC degeneration in basal, middle, and apical regions of the cochlear ducts of isogenic Beethoven mice. At 4 weeks of age, C3H-Tmc1Bth/Bth cochleae had nearly complete IHC degeneration in all three regions, whereas OHCs showed a tonotopic gradient of degeneration with a few percent degeneration in the apical duct, 30% in the middle turn, and 70% in the basal turn (Figure 2). In contrast, C3H-Tmc1+/+ cochleae had no degeneration of IHCs or OHCs at 20 weeks of age. C3H-Tmc1Bth/+ hair cells showed an intermediate phenotype. At all developmental time points, C3H-Tmc1Bth/+ OHC degeneration was limited to the basal region, progressing from 20% degeneration at 4 weeks of age to 40% at 20 weeks of age. C3H-Tmc1Bth/+ IHC degeneration was partial (70%) and mainly restricted to the basal region at 4 weeks of age, but increased in a base-to-apex direction with increasing age. By 20 weeks of age, IHC degeneration was essentially complete in the basal and middle regions, and 40% complete in the apical region.
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40 vs. 0% in the middle region, respectively. There were no significant differences in OHC degeneration between the two hybrid groups: P = 0.3068, apical; P = 0.2477, middle; P = 0.9639, basal. Whereas OHC degeneration was similar among the three rows at any particular location in both hybrid groups, the inner row was most affected and the outer row was least affected in C3H-Tmc1Bth/+ cochleae (not shown).
Outer hair cell function:
We measured DPOAEs to determine the effect of strain background on OHC function in Beethoven mice. Four- and 12-week-old C3H-Tmc1Bth/Bth mice had DPOAE amplitudes that were not different from the noise floor of –10 to –20 dB SPL (Figure 3, A and C) in comparison to robust DPOAEs of >30 dB SPL that increased slightly in amplitude from 4 through 32 weeks of age in Tmc1+/+ mice (Figure 3, A and D). C3H-Tmc1Bth/+ DPOAEs had a similar configuration and age dependence (Figure 3, A and B) but with 5 dB lower amplitudes than wild-type DPOAEs at most frequencies. At 4 weeks of age, these differences were significant (P < 0.05) for all f2 frequencies above 5 kHz. There were no differences at low f2 frequencies since even wild-type DPOAEs are typically undetectable above acoustic noise for f2 
5 kHz (Figure 3A).
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To map loci modifying OHC degeneration in Tmc1Bth/+ mice, we measured DPOAEs of 144 [(C/B)F1 x C]N2-Tmc1Bth/+ and 180 [(C/D)F1 x C]N2-Tmc1Bth/+ backcross progeny (Figure 5). The continuous distribution of DP-grams was not consistent with a simple model of mono- or digenic inheritance of modifier alleles, so we analyzed a three-frequency DPOAE amplitude average as a quantitative trait (see MATERIALS AND METHODS). The heritability of this trait was 0.82 in [(C/B)F1 x C]N2-Tmc1Bth/+ mice and 0.86 in [(C/D)F1 x C]N2-Tmc1Bth/+ mice. The subtotal heritability is consistent with the degree of variation of DPOAE amplitudes in F1 hybrid mice (Figure 4).
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To detect additional modifier loci, we performed a genomewide QTL association analysis on a total of 144 [(C/B)F1 x C]N2-Tmc1Bth/+ and 125 [(C/D)F1 x C]N2-Tmc1Bth/+ backcross progeny (Table 5, Figure 6). Interval mapping confirmed the strong association on chromosome 11 in the DBA/2J backcross progeny (Figure 6B) and weaker but significant association with chromosome 2 in the C57BL/6J backcross progeny (Figure 6A). Although the appearance of two peaks might indicate that more than one locus may exist in each interval, genotype analysis of additional markers (listed in Table 4) and additional animals (55 [(C/D)F1 x C]N2-Tmc1Bth/+ mice) could not significantly demonstrate the existence of two distinct loci within either broad interval. Tmc1m1 and Tmc1m2 accounted for 16 and 19% of the observed trait variation in the respective N2 backcross progeny (Table 5). We also detected significant associations of reduced DPOAE amplitudes with DBA/2J alleles of markers on chromosomes 12 (Tmc1m3; Figure 6C) and 5 (Tmc1m4; Figure 6D) that accounted for 10 and 9% of the observed trait variation, respectively (Table 5). Finally, we observed suggestive associations, which failed to reach statistical significance, of increased DPOAE amplitudes with C57BL/6J alleles of markers on chromosomes 15 (Figure 6E) and 17 (Figure 6F) that could account for 9 and 8%, respectively, of the observed trait variation (Table 5).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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The combination of intact OHC function with elevated hearing thresholds in human patients has been referred to as auditory dyssynchrony or auditory neuropathy (STARR et al. 1996), which can also affect speech perception ability. Auditory neuropathy is a misleading misnomer when a similar phenotype, albeit with better speech perception, results from IHC dysfunction. It is unknown if DFNA36 or DFNB7/B11 phenotypes clinically present with intact DPOAEs. However, speech perception is not affected in DFNA36 (MAKISHIMA et al. 2004), while the onset, severity, and nonauditory communication rehabilitation of DFNB7/B11 subjects prohibits assessment of their speech perception (KURIMA et al. 2002). Only two autosomal nonsyndromic hearing loss loci in humans are known to be associated with an auditory neuropathy/dyssynchrony phenotype: one is autosomal dominant (AUNA1) (KIM et al. 2004) and the other is autosomal recessive (DFNB9) (RODRIGUEZ-BALLESTEROS et al. 2003; VARGA et al. 2003). The contributions of these loci to the genetic load of nonsyndromic auditory neuropathy/dyssynchrony are unknown, and it remains possible that some other cases might be caused by TMC1 mutations.
In comparison to isogenic C3H-Tmc1Bth/+ mice, we observed a different pattern of Tmc1Bth/+ hair cell degeneration on C57BL/6J or DBA2/J F1 hybrid backgrounds. Although IHC degeneration was essentially unchanged, OHCs degenerated more rapidly in a base-to-apex direction along the cochlear ducts of hybrid mutant mice. We have now mapped at least four distinct loci with different strain alleles that differentially modify OHC function in Beethoven mice. Tmc1m1 and potential loci on chromosomes 15 and 17 could collectively account for 33% of the observed phenotypic variation in [(C/B)F1 x C]N2-Tmc1Bth/+ mice, whereas Tmc1m2, Tmc1m3, and Tmc1m4 could account for up to 38% of the variation in [(C/D)F1 x C]N2-Tmc1Bth/+ mice (Table 5). Given the high heritability of the trait, these findings likely reflect the existence of other genetic modifiers with minor effects. Our initial impression of only one or two modifier loci may have been due to inadequate numbers (20–40) of N2 progeny in preliminary analyses. Additional modifier loci might be identified using other mouse strains or an intercross mapping strategy, which could also distinguish additive (semidominant) from dominant effects of the alleles. It is also possible that hair cell degeneration itself may be a better quantitative trait to detect and map modifiers. Finally, our strategy requiring selection for Tmc1Bth in N2 mice would be unlikely to detect potential modifier loci linked to Tmc1 on chromosome 19.
Mitochondrial mutations have been implicated in some human auditory neuropathy phenotypes (ISHIKAWA et al. 2002; WANG et al. 2005) and in modification of age-related hearing loss in mice (JOHNSON et al. 2001). However, we did not observe an effect of gender on the phenotype of F1 mice or N2 mice, or an effect of parental gender on N2 phenotypes (not shown). These findings indicate there was either no effect or a comparatively minor effect of sex-linked or mitochondrial modifiers in our backcross progeny.
The cochlear locations of OHC loss in Beethoven F1 hybrid mice were consistent with the affected frequencies of hearing and OHC function. ABR thresholds were affected in a high-to-low-frequency gradient (not shown) correlating with the base-to-apex gradient of both IHC and OHC degeneration. Similarly, low-frequency DPOAEs were intact and OHCs were preserved in the apical cochlea, where low-frequency stimuli are transduced. Conversely, the effect of the F1 hybrid background on DPOAE amplitudes was greatest at higher measured f2 frequencies (Figure 4). Because the upper frequency limit of reliable DPOAE measurements in our experiments was 16 kHz (see MATERIALS AND METHODS), the capability to accurately measure DPOAEs at f2 
16 kHz in the future might also reveal diminution of DPOAE amplitudes at these frequencies in the hybrid mutants.
The comparatively modest elevation of ABR thresholds, which is similar in different hybrid Beethoven mice, likely reflects a predominant effect of IHC degeneration and loss of afferent function upon overall hearing. Indeed, we were unable to identify any modifier loci using ABR thresholds as a quantitative trait (not shown). This small effect of genetic background upon hearing thresholds in Beethoven mice is consistent with the uniformity of the DFNA36 phenotype among affected members of a single family (MAKISHIMA et al. 2004).
The broad chromosomal intervals of the Tmc1m loci (Figure 6) contain many excellent candidate genes and loci for other auditory disorders, including several implicated in auditory function and hearing loss. For example, the age-related hearing loss locus Ahl2 overlaps with Tmc1m4 on chromosome 5 (JOHNSON and ZHENG 2002). Another example is Tmc2, a closely related paralog of Tmc1 (KURIMA et al. 2002, 2003). Tmc2 is expressed in cochlear hair cells and colocalizes with Tmc1m1, but we found no strain-specific coding or splice site sequence variants of Tmc2 correlated with the phenotypic effects of Tmc1m1 (not shown). Similarly, we found no explanatory strain-specific variants of Myo1c (not shown), which colocalizes with Tmc1m2 and has been implicated in hair cell stereocilia function (HOLT et al. 2002). Crosses with other strains and interval-specific haplotype analysis could narrow and potentially shift the Tmc1m intervals and our search for causative variants, especially if any of the intervals (Figure 6) are resolved into multiple discrete loci (DIPETRILLO et al. 2005).
The microtubule-associated protein gene 1a (Mtap1a) that modifies hearing loss in tubby mice (IKEDA et al. 2002) also colocalizes with Tmc1m1. Although the C57BL/6J variant of Mtap1a is a recessive susceptibility allele for hearing loss in tubby mice (IKEDA et al. 2002), the genotypes and phenotypic effects of C3HeB/FeJ or DBA/2J alleles at this locus have not been reported but warrant future study. Other known modifiers of hearing loss include Cdh23 and Atp2b2 (NOBEN-TRAUTH et al. 2003; SCHULTZ et al. 2005), which do not colocalize with any of the Tmc1m loci. We cannot rule out Atp2b2 as a potential modifier since there may not be functionally significant differences in Atp2b2 among the background strains we studied. In contrast, although DBA/2J and C57BL/6J carry the recessive age-related hearing loss (ahl) allele of Cdh23 and C3HeB/FeJ does not (NOBEN-TRAUTH et al. 2003), potential modifier loci with recessive DBA/2J or C57BL/6J alleles would not have been detected with our backcross design. Future studies are needed to identify potential interactions of these known modifiers of hearing loss with Tmc1Bth.
We anticipate that identifying the modifiers of Beethoven hair cell degeneration will be difficult, but the potential therapeutic insights offered by genetic modifiers justify a search for them (NADEAU 2005). Since the polygenic modification of OHC degeneration in Beethoven mice is consistent with the presumed complex etiology of OHC degeneration in common SNHL phenotypes in humans, the human orthologs of Beethoven modifiers will be excellent candidates to screen for these complex traits or the phenotypic variation associated with monogenic SNHL in humans (SCHULTZ et al. 2005).
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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FOOTNOTES |
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2 Present address: Department of Physiology, University of Kentucky, Lexington, KY 40536-0298.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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