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, Pax3(p)(Sd)), coisogenic on the C57BL/6J (B-6) genetic background, produces in heterozygotes a white belly spot with 100% penetrance and very few other anomalies. By contrast, many Sp(d)/+ BC1 progeny [F-1 female Sp(d)/+ (female Sp(d)/+ B-6 x male +/+ Mus spretus) x male +/+ B-6] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC1 Sp(d)/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of the Sp(d)/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact with Sp(d) 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 Sp(d) and determines the presence and size of the white belly spot. The viability of BC1 mice is influenced by at least three factors: Sp(d), 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. (C) 1996 Academic Press, Inc.
