ENU mutagenesis reveals a highly mutable locus on mouse Chromosome 4 that affects ear morphogenesis |
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Authors: | Amy E Kiernan Alexandra Erven Stéphanie Voegeling Jo Peters Pat Nolan Jackie Hunter Yvonne Bacon Karen P Steel Steve D M Brown Jean-Louis Guénet |
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Institution: | (1) MRC Institute of Hearing Research, University Park, NG7 2RD Nottingham, UK;(2) MRC Mammalian Genetics Unit, Harwell, 0X11 ORD Didcot, Oxfordshire, UK;(3) GlaxoSmithKline, New Frontiers Science Park, CM19 5AW Harlow, Essex, UK;(4) Unité de Génétique des Mammiféres, Institut Pasteur, 25 rue du Docteur Roux, Cedex 15, F-75015 Paris, France |
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Abstract: | Chemical mutagenesis followed by screening for abnormal phenotypes in the mouse holds much promise as a method for revealing
gene function. This method is particularly well-suited for discovering genes involved in hearing or balance function, as these
defects are relatively easy to screen for in the mouse. We report here the inner ear abnormalities and genetic localization
of seven new dominant mutations created by ENU mutagenesis. All seven mutant stocks were identified because of circling and/or
head-weaving behavior, which is an indication of balance dysfunction. Investigation of the inner ears of the seven mutant
stocks revealed very similar lateral and posterior semicircular canal defects. Studies of the development of the canals in
one mutant stocks revealed that the affected canals showed reduced outgrowth and delayed canal fusion. Physiological studies
performed in one mutant stock showed raised average compound-action-potential thresholds of approximately 10–20 dB sound pressure
level (SPL) (depending on frequency), indicating a mild hearing impairment, although scanning electron microscopy performed
in several of the mutant stocks revealed no obvious structural defects in the organ of Corti. All seven mutations mapped to
the proximal portion of Chromosome (Chr) 4, near the centromere. On the basis of their similar phenotype and map location,
we suggest that the seven mutant genes may be allelic and represent a highly mutable locus on Chr 4 that may be particularly
susceptible to ENU-induced mutation on the BALB/c genetic background. |
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