Genetic Modification of Hearing in Tubby Mice: Evidence for the Existence of a Major Gene (moth1) Which Protects Tubby Mice from Hearing Loss (original) (raw)
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Strain background effects and genetic modifiers of hearing in mice
Brain Research, 2006
Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positionalcandidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23 753A/G). This variant also was shown to modify hearing loss associated with the Atp2b2 dfw-2J and Mass1 frings mutations. The hearing modifier (Moth1) of tubby (Tub tub) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2 dfw-2J-Cdh23 753A/G interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.
Hearing Research, 2001
The modifier of deaf waddler (mdfw) and age-related hearing loss (Ahl) loci were both discovered as inbred strain polymorphisms that affect hearing loss in mice. Both loci map to the same position on chromosome (Chr) 10. The mdfw locus interacts epistatically with the deaf waddler (dfw) mutation on Chr 6, and the Ahl locus is a major contributor to AHL in several inbred strains. To investigate the possibility of allelism, we examined the correspondence of mdfw and Ahl phenotypes among 12 inbred mouse strains. The effects of strain-specific mdfw alleles on hearing loss were assessed in dfw 2J /+ F1 hybrids produced from mating BALB-dfw 2J /+ mice with mice from each of 12 inbred strains. F1 hybrids were then assessed for hearing by auditory-evoked brainstem response threshold analysis and classified as dfw 2J /+ or +/+ by polymerase chain reaction typing. Heterozygosity for dfw 2J accelerated hearing loss in F1 hybrids derived from all strains tested, except those produced with the B6.CAST + Ahl congenic strain. dfw 2J /+ F1 hybrids derived from parental strains 129P1/ ReJ, A/J, BUB/BnJ, C57BR/cdJ, DBA/2J, NOD/LtJ and SKH2/J exhibited a severe hearing loss by 12 weeks of age. Those derived from strains 129T2/SvEmsJ, C3H/HeJ, CBA/CaJ and NON/LtJ exhibited only a slight to intermediate hearing loss at that age. The hearing loss associated with these strain-specific mdfw alleles corresponds with previously determined Ahl allele effects, providing additional evidence that mdfw and Ahl are manifestations of the same gene. A functional relationship therefore may exist between the Ca 2+ transporting activity of the dfw gene (Atp2b2) and AHL.
Microtubule-associated protein 1A is a modifier of tubby hearing (moth1)
Nature Genetics, 2002
Once a mutation in the gene tub was identified as the cause of obesity, retinal degeneration and hearing loss in tubby mice 1-2 , it became increasingly evident that the members of the tub gene family (tulps) influence maintenance and function of the neuronal cell lineage 3-6 . Suggested molecular functions of tubby-like proteins include roles in vesicular trafficking 4,7 , mediation of insulin signaling 8 and gene transcription 9,10 . The mechanisms through which tub functions in neurons, however, have yet to be elucidated. Here we report the positional cloning of an auditory quantitative trait locus (QTL), the modifier of tubby hearing 1 gene (moth1) 11 , whose wildtype alleles from strains AKR/J, CAST/Ei and 129P2/OlaHsd protect tubby mice from hearing loss. Through a transgenic rescue experiment, we verified that sequence polymorphisms in the neuronspecific microtubule-associated protein 1a gene (Mtap1a) observed in the susceptible strain C57BL/6J (B6) are crucial for the hearing-loss phenotype. We also show that these polymorphisms change the binding efficiency of MTAP1A to postsynaptic density molecule 95 (PSD95), a core component in the cytoarchitecture of synapses. This indicates that at least some of the observed polymorphisms are functionally important and that the hearing loss in C57BL/6J-tub/ tub (B6-tub/tub) mice may be caused by impaired protein interactions involving MTAP1A. We therefore propose that tub may be associated with synaptic function in neuronal cells.
Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses
Hearing Research, 1999
The common occurrence of hearing loss in both humans and mice, and the anatomical and functional similarities of their inner ears, attest to the potential of mice being used as models to study inherited hearing loss. A large-scale, auditory screening project is being undertaken at The Jackson Laboratory (TJL) to identify mice with inherited hearing disorders. To assess hearing sensitivity, at least five mice from each inbred strain had auditory brainstem response (ABR) thresholds determined. Thus far, we have screened 80 inbred strains of mice; 60 of them exhibited homogeneous ABR threshold values not significantly different from those of the control strain CBA/CaJ. This large database establishes a reliable reference for normal hearing mouse strains. The following 16 inbred strains exhibited significantly elevated ABR thresholds before the age of 3 months: 129/J, 129/ReJ, 129/ SvJ, A/J, ALR/LtJ, ALS/LtJ, BUB/BnJ, C57BLKS/J, C57BR/cdJ, C57L/J, DBA/2J, I/LnJ, MA/MyJ, NOD/LtJ, NOR/LtJ, and SKH2/J. These hearing impaired strains may serve as models for some forms of human non-syndromic hearing loss and aid in the identification of the underlying genes.
An Age-Related Hearing Protection Locus on Chromosome 16 of BXD Strain Mice
Neural Plasticity, 2020
Inbred mouse models are widely used to study age-related hearing loss (AHL). Many genes associated with AHL have been mapped in a variety of strains. However, little is known about gene variants that have the converse function—protective genes that confer strong resistance to hearing loss. Previously, we reported that C57BL/6J (B6) and DBA/2J (D2) strains share a common hearing loss allele in Cdh23. The cadherin 23 (Cdh23) gene is a key contributor to early-onset hearing loss in humans. In this study, we tested hearing across a large family of 54 BXD strains generated from B6 to D2 crosses. Five of 54 strains maintain the normal threshold (20 dB SPL) even at 2 years old—an age at which both parental strains are essentially deaf. Further analyses revealed an age-related hearing protection (ahp) locus on chromosome 16 (Chr 16) at 57~76 Mb with a maximum LOD of 5.7. A small number of BXD strains at 2 years with good hearing correspond roughly to the percentage of humans who have good h...
Identification of 17 hearing impaired mouse strains in the TMGC ENU-mutagenesis screen
Hearing Research, 2006
The Tennessee Mouse Genome Consortium (TMGC) employed an N-ethyl-N-nitrosourea (ENU)-mutagenesis scheme to identify mouse recessive mutants with hearing phenotypes. We employed auditory brainstem responses (ABR) to click and 8, 16, and 32 kHz stimuli and screened 285 pedigrees (1819 mice of 8-11 weeks old in various mixed genetic backgrounds) each bred to carry a homozygous ENU-induced mutation. To define mutant pedigrees, we measured P12 mice per pedigree in P2 generations and used a criterion where the mean ABR threshold per pedigree was two standard deviations above the mean of all offspring from the same parental strain. We thus identified 17 mutant pedigrees (6%), all exhibiting hearing loss at high frequencies (P16 kHz) with an average threshold elevation of 30-35 dB SPL. Interestingly, four mutants showed sex-biased hearing loss and six mutants displayed wide range frequency hearing loss. Temporal bone histology revealed that six of the first nine mutants displayed cochlear morphological defects: degeneration of spiral ganglia, spiral ligament fibrocytes or inner hair cells (but not outer hair cells) mostly in basal turns. In contrast to other ENU-mutagenesis auditory screens, our screen identified high-frequency, mild and sex-biased hearing defects. Further characterization of these 17 mouse models will advance our understanding of presbycusis and noise-induced hearing loss in humans.
Alleles that modulate late life hearing in genetically heterogeneous mice
Neurobiology of Aging, 2012
A genetically heterogeneous population of mice was tested for hearing at 8, 18 and 22 months by auditory brainstem response (ABR), and genotyped at 128 markers to identify loci that modulate late life hearing loss. Half of the test mice were exposed to noise for 2 hr at age 20 months. Polymorphisms affecting hearing at 18 months were noted on chromosomes 2, 3, 7, 10, and 15. Most of these loci had effects only on responses to 48 kHz stimuli, but a subset also influenced the ABR at lower frequencies. Loci on chromosomes 4, 10, 12, and 14 had significant effects on hearing at 22 months in noise-exposed mice, and loci on chromosomes 10 and 11 had effects on mice not exposed to noise. Outer hair cell loss was modulated by polymorphisms on chromosomes 10, 11, 12, 17, and 19. Resistance to age-related hearing loss is thus modulated by a set of genetic effects, some age-specific, some frequency specific, some dependent on prior exposure to noise, and some of which compromise survival of cochlear hair cells.
Fine Genetic and Comparative Mapping of the Deafness Mutation Ames waltzer on Mouse Chromosome 10
Genomics, 1998
head tossing, and hyperactivity. Females are often poor The Ames waltzer (av) mouse mutant is an autosomal mothers. av mice swim only with difficulty and circle recessive deafness mutation on mouse Chromosome afloat. av 2J mice are reportedly more severely affected 10. Previously, av had not been mapped relative to moand sink in the swim test (Cook and Lane, 1993). lecular markers. We have performed an intersubspe-Previously, the av locus had been localized with low cific backcross with Mus musculus castaneus and resolution to phenotypic markers in the central region mapped microsatellite markers in this cross. Toothof Chromosome 10. It mapped about 43 cM proximal pick PCR on previously frozen tissue samples from offto silver (si) (Schaible, 1961) and 21-31 cM distal to spring was used as an efficient strategy to screen a the dystonia mutation, now known as laminin, a 2 (Lalarge number of animals quickly. In 1258 progeny ma2 dy) (Russell and Southard, 1966). No closely linked tested we found three recombinants for each of the markers have been reported. flanking markers D10Mit199 and D10Mit64. In addi-Central mouse Chromosome 10 has homologies to tion, nine different genes (Ank3, Bcr, Gnaz, Tfam, Mif, several human chromosomes (10q21-q22, 22q11, Mmp11, Dcoh, Pyp, and Gstt2) were mapped and elimi-21q22, 19p13) (Taylor et al., 1996). Human recessive nated genetically as candidate genes for av. av had deafness loci have been mapped to both 10q21 and been discussed as a potential mouse model for the hu-21q22 (Wayne et al., 1996; Chaib et al., 1996; Veske et man deafness loci Usher syndrome type ID (USH1D) al., 1996; Bonne-Tamir et al., 1996). In this study we and DFNB12. Comparative mapping shows that av report the fine genetic mapping of the av locus to closely maps near an evolutionary break point and makes it linked markers. Fine genetic mapping will not only unlikely that those loci are human homologues of av. facilitate positional cloning, but will also help to deter-A human homologue of av is predicted to lie either mine which, if any, human recessive deafness locus on 22q11.2 or on 10q21. The orientation of conserved linkage groups between these two human chromo-may be a homologue of av. somal regions relative to mouse Chromosome 10 was determined. ᭧ 1998 Academic Press MATERIALS AND METHODS Intersubspecific backcross. An intersubspecific backcross with Offspring were scored phenotypically at age 5-6 weeks. Two mea-ditory function in av mice (Osako and Hilding, 1971, sures were used: First it was observed if the animal was actively the only published description of Ames waltzer). Inicircling. If so, it was scored affected (av/av). If it was not circling it tially, all hair cells are formed but after about the 10th was tested for pinna response: A loud noise was generated out of day after birth the fluid spaces in the organ of Corti vision of the animal and it was observed if the ear (pinna) or the fail to develop. Subsequently during maturation the whole animal moved in response to the noise. This was repeated several times. Animals that responded were scored as unaffected (av/ spiral ganglion cells degenerate with gradual loss of /), those that did not, as affected (av/av). Most but not all animals hair cells. The permeability of the stria vascularis apgave consistent results. Once animals were scored, lung, liver, and pears to be normal (Osako and Hilding, 1971). In addispleen were removed and frozen in liquid nitrogen and stored at tion to deafness, av mice show typical circling behavior, 080ЊC for subsequent DNA analyses. DNA preparation. Small-scale DNA preparation was performed from an aliquot (1/10
A locus on distal chromosome 10 (ahl4) affecting age-related hearing loss in A/J mice
Neurobiology of Aging, 2009
The ahl locus, shown to be a strain-specific Cdh23 dimorphism, contributes to age-related hearing loss in many inbred mouse strains. A/J mice begin to lose hearing by four weeks of age, much earlier than C57BL/6J (B6) mice, although both strains have the same Cdh23 ahl variant. Here, we use recombinant inbred strains, chromosome substitution strains, and a linkage backcross to map a locus on distal Chromosome 10, designated ahl4, that contributes to the early-onset hearing loss of A/J mice. Cochleae of 9-week-old A/J mice exhibit inner and outer hair cell loss from the basal turn through the apical turn, with outer hair cell loss at the base being severest. To quantify the progression of hair cell loss, cytocochleograms were evaluated from 0 to 20 weeks of age. AJ mice showed evidence of hair cell loss in the base of the cochlea as early as 14 days of age and the magnitude and extent of loss increased rapidly during the following 2-5 months. Hair cell loss occurred earlier and was much more severe and widespread in A/J mice than in B6 mice during the first 5 months of age. Spiral ganglion neurons, cells of the stria vascularis, and vestibular hair cell densities, however, appeared normal in 20-week-old A/J mice.