mdfw:A Deafness Susceptibility Locus That Interacts with Deaf Waddler (dfw)

The deaf waddler (dfw) mutation is a model system to study the biology of neuroepithelial hearing defects in mice. Here we describe the identification and characterization of a new allele of deaf waddler (dfw^2J) and present evidence for a hearing susceptibility locus (mdfw) that interacts withdfw.We found that CBy-dfw^2J/dfw^2Jhomozygotes exhibit no discernible auditory brainstem responses (ABR) to sound pressure level stimuli up to 100 dB, indicating a profound deafness. Interestingly, the ABR in CBy-dfw^2J/+ heterozygotes is also abnormal, showing age-dependent elevated thresholds characteristic of a progressive hearing loss. When outcrossed onto the CAST/Ei strain, only 24% of the F2 CBy/CAST-dfw^2J/+ heterozygotes displayed increased ABR thresholds, suggesting that a second locus, controlling hearing function indfw^2J/+ heterozygotes, was segregating in the CBy/CAST-dfw^2Jintercross. By linkage analysis, we localized this locus (mdfw) to Chromosome 10, between markersD10Mit127andD10Mit185,within a 4.0 ± 1.1 cM genetic interval. All CBy/CAST-dfw^2J/+ heterozygotes that develop hearing loss are homozygous for the CBy-derived recessive allele (mdfw^C). In contrast, CBy/CAST-dfw^2J/+ heterozygotes expressing even a single copy of the CAST/Ei-derivedmdfwallele (Mdfw) retain their normal hearing function. Our results reveal an epistatic relationship between themdfwand thedfwgenes and provide a model system to study nonsyndromic hearing loss in mice.