Deaf ballerina (Dfb), a new spontaneous mouse mutation with phenotype and map position similar to wheels and whirligig (Chd7Whi).
Leona H. Gagnon, Leah Davis,* Sandra J. Gray and Kenneth R. Johnson
Source of Support: This research was supported by NIH/NCRR grant RR01183 to the Mouse Mutant Resource (M.T. Davisson, PI) and NIH/NIDCD grant DC04301 (K.R. Johnson, PI).
*Summer Student internship program supported by the National Science Foundation, the Barbara H. Sanford Endowed Scholarship Fund, and the Horace W. Goldsmith Foundation
Mutation (allele) symbol: Dfb
Mutation (allele) name: Deaf ballerina
Gene symbol:
Strain of origin: BALB/cJ
Current strain name: BALB-Dfb/J
Stock #: 006274 (view JAX® Mice Data Sheet for additional information including Price and Supply Information) NOTE: As of Feb.5, 2005 will be available as cryopreserved sperm only. DNA samples are available from the Jackson Laboratory DNA Resource.
Phenotype categories: neurological/behavioral: motor capabilities/coordination/movement anomalies/deafness/head bobbing
Origin and Description
The dominantly inherited spontaneous mouse mutation deaf ballerina (Dfb) was discovered in an inbred colony of BALB/cJ mice at the Jackson Laboratory in 2002. In order to improve fecundity, mutant mice were successively outcrossed to the BALB/cByJ inbred strain. Mutant mice display circling and head tossing behavior typical of mice with inner ear defects. Hearing was assessed by auditory brainstem response (ABR). Analysis of hearing from four mutant mice (Dfb/+) and three controls (+/+) revealed that the mutant mice were deaf (ABR thresholds > 50 dB above normal) while the littermate controls retained good hearing (normal ABR thresholds). All 13 Dfb mutants examined were missing a corpus callosum in the brain. Dfb/+ males are viable and fertile, although under gross examination their testes appeared smaller than those of +/+ littermates. Female (Dfb/+) mutants are viable but do not breed. Female infertility precluded an investigation of homozygous viability or lethality. Heterozygotes of both sexes are slightly smaller with less fat than control littermates.
Genetic Analysis
To determine the mode of inheritance of deaf ballerina, a mutant mouse (Dfb/+) was mated with a normal (+/+) C57BL/6J mouse. Approximately 50% of the F1 generation was mutant, indicating a dominant mode of inheritance. A linkage-cross was then established by mating the F1 generation mutants (Dfb/+) to wild-type (+/+) BALB/cByJ mice. All backcross (N2) progeny were saved (N=183) and evaluated independently for circling behavior, hearing threshold and the presence of a corpus callosum. ABR tests revealed that all circling mice had severe hearing loss with thresholds 20-40 dB above those of non-circling mice; however, this impairment was less severe than that observed in Dfb/+ mice on the pure BALB background. Approximately 85% (58/68) of the mutants from the linkage cross were missing the corpus callosum, again showing reduced penetrance of the phenotype in the backcross progeny.
Using our standard mapping practice, we genetically mapped Dfb to proximal Chromosome 4, in the region where the mouse Chd7 gene is located (8.6 Mb, Ensembl, NCBI m36 mouse assembly), between the centromere and microsattelite marker D4MIT181 (9.1 Mb).
Pathology
Coronal sections of the brain stained with luxol-fast blue/cresyl violet (LFB/CV) showed an absence of the corpus callosum in all of the inbred strain mutants and the majority (~85%) of the mutant mice from the linkage cross (see photo). Approximately 3% of the control linkage mice were missing the corpus callosum, which is consistent with the frequency of BALB/cByJ strain mice missing this structure. No other midline defects were detected.
Ophthalmic examination of the eye revealed some pigment loss in the retina of mutant mice, but this may be due to or exacerbated by the albino coat color of the BALB/cByJ mouse. An electroretinogram (ERG) gave a normal response to a light flash indicating normal retinal function.
Discussion
The phenotype and dominant inheritance of Dfb mice are similar to those of mice with mutations in the Chd7 gene (Bosman et al., 2005), including dizzy (Dz), eddy (Edy), and cyclone (Cy) and the unproven alleles wheels (Whl) and wheels-like (Whll). The absent corpus callosum and the extreme degree of hearing loss of Dfb mutants, however, have not been previously described in Chd7 mouse mutants. Mutations in the CHD7 gene in humans are known to underlie CHARGE syndrome (Vissers et al., 2004). Although heart, eye and nasal abnormalities were not detected in Dfb mice, this could be due to differences in inbred strain backgrounds or to the highly variable phenotypes associated with Chd7 mutations in mice and with human CHARGE syndrome.
Acknowledgments
We thank Dolores Shields for identifying the first mutant animals, Heping Yu and Chantal Longo-Guess for ABR analysis, Norm Hawes for ophthalmic evaluation, Roderick Bronson and Coleen Marden for pathological assistance.
References
Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP (2005) Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Hum Mol Genet 14:3463-76.
Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36:955-7.
