Waardenburg syndrome is characterized by dystopia canthorum, pigmentary disturbances and sensorineural deafness. This disorder is inherited in an autosomal dominant mode with incomplete penetrance and variable expression. The human paired-box homeotic gene 3 (
PA3)3, a candidate for Waardenburg syndrome type I (WS I) was isolated by means of the rapid amplification of cDNA ends (RACE) procedure. Fluorescence in situ hybridization using a cosmid clone containing
PAX3 as a probe demonstrated that the gene is located to chromosome 2q35. Analysis of gene expression in various human adult tissues by reverse transcriptase-based polymerase chain reaction (RT-PCR) revealed tissue-specific expression of this gene. A 684-bp transcript was generated only from the cerebellum and skeletal muscle by alternative splicing. Analysis of 17 WS families by PCR-SSCP and subsequent sequencing revealed that in one family, affected members had a point mutation, A to T transversion, which leads to an Ile to Phe substitution at codon 59.Another family had an A to T transversion, at the splice acceptor site at the intron 1-2 boundary.
The gene product of
PAX3 is a transcription factor that is active in early embryogenesis. However, little has been known about the target gene (s) of the product. Although several different mutations in
PAX3 have been reported in WS I patients, no relationship was demonstrated between individual
PAX3 mutations and particular clinical phenotypes. This unusual phenomenon in WS I may be explained by “haploinsufficiency with dosagesensitivity”: different tissues show differential sensitivity to the dose of
PAX3 gene product. Alternatively, the phenomenon is due to dominant negative effect of the mutant gene.
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