title: A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome.
abstract: Neural tube defects (NTD) are among the most prevalent congenital malformations in man. Based on the molecular defect of Splotch, an established mouse model for NTD, and on the clinical association between NTD and Waardenburg syndrome (WS), mutations in the PAX3 gene can be expected to act as factors predisposing to human NTD. To test this hypothesis, 39 patients with familial NTD were screened by SSC analysis for mutations in exons 2 to 6 of the human PAX3 gene. One patient with lumbosacral meningomyelocele was identified with a 5 bp deletion in exon 5 approximately 55 bp upstream of the conserved homeodomain. The deletion causes a frameshift with a stop codon almost immediately after the mutated site. Clinical investigation of the index patient indicated mild signs of WS type I. Varying signs of this syndrome were found to cosegregate with the mutation in the family. Our results support the hypothesis that mutations in the gene for PAX3 can predispose to NTD, but also show that, in general, mutations within or near the conserved domains of the PAX3 protein are only very infrequently involved in familial NTD.
authors.affiliation: Department of Human Genetics, University Hospital Nijmegen, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: Hol
authors.forename: B C
authors.initials: BC
authors.lastname: Hamel
authors.forename: M P
authors.initials: MP
authors.lastname: Geurds
authors.forename: R A
authors.initials: RA
authors.lastname: Mullaart
authors.forename: F G
authors.initials: FG
authors.lastname: Barr
authors.forename: R A
authors.initials: RA
authors.lastname: Macina
authors.forename: E C
authors.initials: EC
authors.lastname: Mariman
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D016137:Spina Bifida Cystica / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: 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