title: Molecular basis of splotch and Waardenburg Pax-3 mutations.
abstract: Pax genes control certain aspects of development, as mutations result in (semi)dominant defects apparent during embryogenesis. Pax-3 has been associated with the mouse mutant splotch (Sp) and the human Waardenburg syndrome type 1 (WS1). We have examined the molecular basis of splotch and WS1 by studying the effect of mutations on DNA binding, using a defined target sequence. Pax-3 contains two different types of functional DNA-binding domains, a paired domain and a homeodomain. Mutational analysis of Pax-3 reveals different modes of DNA binding depending on the presence of these domains. A segment of Pax-3 located between the two DNA-binding domains, including a conserved octapeptide, participates in protein homodimerization. Pax-3 mutations found in splotch alleles and WS1 individuals change DNA binding and, in the case of a protein product of the Sp allele, dimerization. These findings were taken as a basis to define the molecular nature of the mutants.
authors.affiliation: Max-Planck-Institute for Biophysical Chemistry, Department of Molecular Cell Biology, Göttingen, Federal Republic of Germany.
authors.forename: G
authors.initials: G
authors.lastname: Chalepakis
authors.forename: M
authors.initials: M
authors.lastname: Goulding
authors.forename: A
authors.initials: A
authors.lastname: Read
authors.forename: T
authors.initials: T
authors.lastname: Strachan
authors.forename: P
authors.initials: P
authors.lastname: Gruss
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005801:Genes, Homeobox; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011485:Protein Binding; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse