Effects ofPax3Modifier Genes on Craniofacial Morphology, Pigmentation, and Viability: A Murine Model of Waardenburg Syndrome Variation

Abstract

Waardenburg syndrome type 1 is caused by mutations inPAX3.Over 50 humanPAX3mutations that lead to hearing, craniofacial, limb, and pigmentation anomalies have been identified. APAX3mutant allele, segregating in a family, can show reduced penetrance and variable expressivity that cannot be explained by the nature of the mutation alone. TheMus musculus Pax3mutationSpd(Splotch-delayed, Pax3[formula]), 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, manySpd/+ BC1progeny [F1♀Spd/+ (♀Spd/+ B6× ♂ +/+Mus spretus) × ♂ +/+ B6] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC1Spd/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of theSpd/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact withSpdto influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. TheA-locus (Agouti) or a gene closely linked toAalso plays a role in determining craniofacial features. At least one additional gene, possibly theA-locus or a gene linked toA,interacts withSpdand determines the presence and size of the white belly spot. The viability of BC1mice is influenced by at least three factors:Spd,A-locus alleles or a gene closely linked to theA-locus, and the sex of the mouse. These BC1mice provide an opportunity to identify genes that interact with and modify the expression ofPax3and serve as a model to identify the genes that modify the expression of humanPAX3mutations.