MUTATIONS IN PAX3 ASSOCIATED WITH WAARDENBURG SYNDROME TYPE-I

Waardenburg syndrome (WS) types I, II, and III (McKusick #14882, #1935 1, and #19350) are related autosomal dominant disorders characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturba nces, 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 h ave not been pinpointed, linkage with the PAX3 locus on chromosome 2q3 5 has been demonstrated, The PAX3 protein is a transcription factor th at contains both a paired-domain and a homeodomain DNA binding motif a nd 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. O ne mutation is a deletion/frameshift in the paired domain of PAX3 and results in a protein without functional DNA binding domains, The secon d mutation is a single-base substitution and results in a premature te rmination codon in the homeodomain of PAX3. This is the first demonstr ation of a mutation in the homeodomain DNA binding motif in this prote in resulting in WS and one of the few examples of a mutation in a home odomain of any protein that results in human disease. (C) 1994 Wiley-L iss, Inc.