title: Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation.
abstract: Waardenburg syndrome type 1 is caused by mutations in PAX3. Over 50 human PAX3 mutations that lead to hearing, craniofacial, limb, and pigmentation anomalies have been identified. A PAX3 mutant allele, segregating in a family, can show reduced penetrance and variable expressivity that cannot be explained by the nature of the mutation alone. The Mus musculus Pax3 mutation Spd (Splotch-delayed, Pax3Spd), coisogenic on the C57BL/6J (B6) genetic background, produces in heterozygotes a white belly spot with 100% penetrance and very few other anomalies. By contrast, many Spd/+ BC1 progeny [F1 female Spd/+ (female Spd/+ B6 x male +/+ Mus spretus) x male +/+ B6] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC1 Spd/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of the Spd/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact with Spd to influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. The A-locus (Agouti) or a gene closely linked to A also plays a role in determining craniofacial features. At least one additional gene, possibly the A-locus or a gene linked to A, interacts with Spd and determines the presence and size of the white belly spot. The viability of BC1 mice is influenced by at least three factors: Spd, A-locus alleles or a gene closely linked to the A-locus, and the sex of the mouse. These BC1 mice provide an opportunity to identify genes that interact with and modify the expression of Pax3 and serve as a model to identify the genes that modify the expression of human PAX3 mutations.
authors.affiliation: Department of Zoology, Michigan State University, East Lansing, Michigan, 48824, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Asher
authors.forename: R W
authors.initials: RW
authors.lastname: Harrison
authors.forename: R
authors.initials: R
authors.lastname: Morell
authors.forename: M L
authors.initials: ML
authors.lastname: Carey
authors.forename: T B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005145:Face / Q000002:abnormalities*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010641:Phenotype; D010859:Pigmentation Disorders / Q000235:genetics; D016133:Polymerase Chain Reaction; D012727:Sex Characteristics; D012886:Skull / Q000002:abnormalities*; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics*; D014960:X Chromosome
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