Mammalian Genome

, Volume 15, Issue 6, pp 424–432 | Cite as

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

  • Nadav Ahituv
  • Alexandra Erven
  • Helmut Fuchs
  • Keren Guy
  • Ruth Ashery–Padan
  • Trevor Williams
  • Martin Hrabe de Angelis
  • Karen B. AvrahamEmail author
  • Karen P. Steel


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.


Compound Action Potential Otosclerosis Endocochlear Potential Msx2 Compound Action Potential Amplitude 



The authors thank Helen Hurst, Stephanie Donaldson, Hubert Schorle, Thomas Schilling, and Ori Brenner for reagents and advice. We would like to acknowledge Rudi Balling for his contribution to setting up the mutagenesis program. This work was supported by the Israel Ministry of Health (K.B.A.), the G.I.F., the German-Israeli Foundation for Scientific Research and Development (K.B.A. and M.H.d.A.), the European Economic Community (QLG2-CT-1999-00988 and BMH4-CT97-2715; K.B.A. and K.P.S.), the UK MRC and Defeating Deafness (K.P.S.), the Israel Science Foundation (401/02; R.A.-P.), and NIH grant DE12728 (T.W.).


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Nadav Ahituv
    • 1
  • Alexandra Erven
    • 2
  • Helmut Fuchs
    • 3
  • Keren Guy
    • 1
  • Ruth Ashery–Padan
    • 1
  • Trevor Williams
    • 4
  • Martin Hrabe de Angelis
    • 3
  • Karen B. Avraham
    • 1
    Email author
  • Karen P. Steel
    • 2
  1. 1.Department of Human Genetics and Molecular Medicine, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.MRC Institute of Hearing ResearchUniversity ParkNottinghamUK
  3. 3.GSF Research Center for Environment and HealthInstitute of Experimental GeneticsNeuherbergGermany
  4. 4.Departments of Craniofacial Biology and of Cell and Structural BiologyUniversity of Colorado Health Sciences CenterDenverUSA

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