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.
Baldwin
C T
CT
Department of Pediatrics, Boston University School of Medicine, Massachusetts 02118.
Lipsky
N R
NR
Hoth
C F
CF
Cohen
T
T
Mamuya
W
W
Milunsky
A
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D017354:Point Mutation; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D004247:DNA