Mutations in PAX3 associated with Waardenburg syndrome type I.

Waardenburg syndrome (WS) types I, II, and III (McKusick #14882, #19351, and #19350) are related autosomal dominant disorders characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Disease causing PAX3 mutations have been identified in a few families from each of the three disease subtypes, WS-I, WS-II, and WS-III. In others, although the mutations have not been pinpointed, linkage with the PAX3 locus on chromosome 2q35 has been demonstrated. The PAX3 protein is a transcription factor that contains both a paired-domain and a homeodomain DNA binding motif and appears to play a key role during embryogenesis. In this report, we describe two mutations in the human PAX3 gene that cause WS type I. One mutation is a deletion/frameshift in the paired-domain of PAX3 and results in a protein without functional DNA binding domains. The second mutation is a single-base substitution and results in a premature termination codon in the homeodomain of PAX3. This is the first demonstration of a mutation in the homeodomain DNA binding motif in this protein resulting in WS and one of the few examples of a mutation in a homeodomain of any protein that results in human disease.