An ENU-induced mutation in AP-2α leads to middle earand 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.

Genome-wide mapping of global-to-local genetic effects on human facial shape

“…These highly specific phenotypic effects might provide important insights about the role of these two genes during human facial morphogenesis and growth. KCTD15 has been shown to regulate TFAP2A , which plays a critical role in neural crest formation 42 and when mutated resulted in reduced snout length in mice among other defects 43 . Perhaps KCTD15 affects nasal tip shape in humans by influencing cartilage proliferation in the nasal septum, whereas SUPT3H exerts its influence on nasal shape by affecting portions of the maxilla and nasal bones.…”

Characterization of the murine Dfna5 promoter and regulatory regions

“…AP-2 α is a transcription factor that functions in a wide range of biological processes, including development, cell cycle control and apoptosis (Hilger-Eversheim et al, 2000). Mutations in AP-2 α lead to conductive hearing loss in mice (Ahituv et al, 2004). NFκB is a transcription factor regulating apoptosis in many cell types.…”

Identification and Analysis of a Conserved Tcfap2a Intronic Enhancer Element Required for Expression in Facial and Limb Bud Mesenchyme

“…Loss or alteration of Tcfap2a expression or function results in a wide range of defects affecting on May 11, 2018 by guest http://mcb.asm.org/ development of the face, limb, eye, ear, neural tube, body wall, and heart outflow tract (1,4,5,14,16,25,26,31,39,43). We have taken a two-pronged approach to identify the cis-regulatory sequences driving the spatiotemporal pattern of Tcfap2a transcription: functional transient transgenic analysis and a comparative sequence analysis to identify conserved elements.…”