Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene

Abstract

WAARDENGURG'S syndrome (WS) is an autosomal dominant combination of deafness and pigmentary disturbances, probably caused by defective function of the embryonic neural crest^1,2. We have mapped one gene for WS to the distal part of chromosome 2 (ref. 3). On the basis of their homologous chromosomal location, their close linkage to an alkaline phosphatase gene, and their related phenotype, we suggested that WS and the mouse mutant Splotch^4,5 might be homologous. Splotch is caused by mutation in the mouse Pax-3 gene^6,7. This gene is one of a family of eight Pax genes known in mice which are involved in regulating embryonic development; each contains a highly conserved transcription control sequence, the paired box⁸. Here we show that some families with WS have mutations in the human homologue⁹ of Pax-3. Mutations in a related gene, Pax-6, which, like Pax-3, has both a paired box and a paired-type homeobox sequence, cause the Small-eye mutation in mice¹⁰ and aniridia inman¹¹. Thus mutations in the Pax genes are important causes of human developmental defects.