title: An ENU-induced mutation in AP-2alpha leads to middle ear and ocular defects in Doarad mice.
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-2alpha ( 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-2alpha. 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.
authors.affiliation: Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.forename: Alexandra
authors.initials: A
authors.lastname: Erven
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Keren
authors.initials: K
authors.lastname: Guy
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002678:Chimera; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics*; D004432:Ear, Middle / Q000002:abnormalities*; D005124:Eye Abnormalities / Q000235:genetics*; D005804:Genes, Lethal; D034381:Hearing Loss / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C493668:Tfap2a protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors