Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability : A murine model of Waardenburg syndrome variation

• Published in: Genomics (San Diego, Calif.) Vol. 34; no. 3; pp. 285 - 298
• Main Authors: ASHER, J. H, HARRISON, R. W, MORELL, R, CAREY, M. L, FRIEDMAN, T. B
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier 15.06.1996
• Subjects: Alleles; Animals; Base Sequence; Biological and medical sciences; Complex syndromes; Crosses, Genetic; Disease Models, Animal; DNA Primers; DNA-Binding Proteins - genetics; Face - abnormalities; Female; Genetic Variation; Genotype; Heterozygote; Humans; Male; Medical genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Paired Box Transcription Factors; PAX3 Transcription Factor; Phenotype; Pigmentation Disorders - genetics; Polymerase Chain Reaction; Sex Characteristics; Skull - abnormalities; Transcription Factors; Waardenburg Syndrome - genetics; X Chromosome; Animal model; Gene interaction; Internal ear disease; Rodentia; Modifier gene; Lethal character; Pigmentation; Genetic disease; Vertebrata; Phenotype; Mammalia; Mouse; Waardenburg syndrome; Gene penetrance; Homeotic gene; ENT disease; Perception hearing loss; Skull; Genetics; Mutation; Complex syndrome; Face; Morphometry
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1006/geno.1996.0289

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.