Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families.

Waardenburg syndrome is an autosomal dominant disorder characterized by sensorineural deafness and pigmentary disturbances. Previous work has linked the disease to PAX3 on chromosome 2, and several mutations within the highly conserved paired-box and octapeptide motifs, but not the homeobox, have been reported. In this report, we have used the published cDNA sequence to further define the genomic structure of PAX3, using inverse PCR. We have identified exon/intron boundaries between exons 5 and 6 and between exons 6 and 7. Further, we have identified the first two mutations within the homeobox in two different families with type 1 Waardenburg syndrome. The first is a point mutation (G-->T) at the first base of exon 6, which substitutes phenylalanine for valine. In another family, we have identified a point mutation (C-->G) within the homebox, in exon 6, which substitutes a glycine for arginine at a highly conserved site. The homeodomain is important in binding of DNA and in effecting transcriptional control. These mutations likely result in structural change within the homeodomain that either change the DNA-binding specificity of the homedomain or reduce the affinity of the PAX3 protein for DNA. These homeodomain mutations should aid in elucidating the role of the homeodomain in the function of the PAX3 protein.