An ENU-induced mutation in AP-2α leads to middle ear and ocular defects in Doarad mice

Nadav Ahituv, Alexandra Erven, Helmut Fuchs, Keren Guy, Ruth Ashery-Padan, Trevor Williams, Martin Hrabe De Angelis, Karen B. Avraham, Karen P. Steel

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

One of the advantages of N-ethyl- N-nitrosourea (ENU)-induced mutagenesis is that, after randomly causing point mutations, a variety of alleles can be generated in genes leading to diverse phenotypes. For example, transcription factor AP-2α (Tcfap2a) null homozygote mice show a large spectrum of developmental defects, among them missing middle ear bones and tympanic ring. This is the usual occurrence, where mutations causing middle ear anomalies usually coincide with other abnormalities. Using ENU-induced mutagenesis, we discovered a new dominant Tcfap2a mutant named Doarad (Dor) that has a missense mutation in the PY motif of its transactivation domain, leading to a misshapen malleus, incus, and stapes without any other observable phenotype. Dor homozygous mice die perinatally, showing prominent abnormal facial structures and ocular defects. In vitro assays suggest that this mutation causes a "gain of function" in the transcriptional activation of AP-2α. These mice enable us to address more specifically the developmental role of Tcfap2a in the eye and middle ear and are the first report of a mutation in a gene specifically causing middle ear abnormalities, leading to conductive hearing loss.

Original languageEnglish
Pages (from-to)424-432
Number of pages9
JournalMammalian Genome
Volume15
Issue number6
DOIs
StatePublished - Jun 2004
Externally publishedYes

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