PAX3 GENE STRUCTURE AND MUTATIONS - CLOSE ANALOGIES BETWEEN WAARDENBURG SYNDROME AND THE SPLOTCH MOUSE

The human PAX3 gene contains a paired box and a paired-type homeobox, and is believed to play a role in pattern formation in the embryo. We describe the exon-intron structure of the homeobox-containing part of PAX3, complementing earlier descriptions of the 5' part of the gene. M utations in PAX3 have been described in patients with Type 1 Waardenbu rg syndrome, who have hearing loss and pigmentary abnormalities, while Splotch mice have mutations in the homologous mouse Pax-3 gene. We de scribe a series of patients who have previously unidentified PAX3 muta tions. These include a chromosomal deletion, a splice-site mutation an d an amino acid substitution which closely correspond to the molecular changes seen in the Splotch-retarded, Splotch and Splotch-delayed mou se mutants respectively. These mutations confirm that Waardenburg synd rome is produced by gene dosage effects and show that the phenotypic d ifferences between Splotch mice and humans with Waardenburg syndrome a re caused by differences in genetic background rather than different p rimary effects of the mutations.