A FRAMESHIFT MUTATION IN THE GENE FOR PAX3 IN A GIRL WITH SPINA-BIFIDA AND MILD SIGNS OF WAARDENBURG-SYNDROME

Neural tube defects (NTD) are among the most prevalent congenital malf ormations in man. Based on the molecular defect of Splotch, an establi shed mouse model for NTD, and on the clinical association between NTD and Waardenburg syndrome (WS), mutations in the PAX3 gene can be expec ted to act as factors predisposing to human NTD. To test this hypothes is, 39 patients with familial NTD were screened by SSC analysis for mu tations in exons 2 to 6 of the human PAX3 gene. One patient with lumbo sacral meningomyelocele was identified with a 5 bp deletion in exon 5 approximately 55 bp upstream of the conserved homeodomain. The deletio n causes a frameshift with a stop codon almost immediately after the m utated site. Clinical investigation of the index patient indicated mil d signs of WS type I. Varying signs of this syndrome were found to cos egregate with the mutation in the family. Our results support the hypo thesis that mutations in the gene for PAX3 can predispose to NTD, but also show that, in general, mutations within or near the conserved dom ains of the PAX3 protein are only very infrequently involved in famili al NTD.