title: PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida.
abstract: From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.
authors.affiliation: Department of Human Genetics, University Hospital Nijmegen, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: Hol
authors.forename: M P
authors.initials: MP
authors.lastname: Geurds
authors.forename: S
authors.initials: S
authors.lastname: Chatkupt
authors.forename: Y Y
authors.initials: YY
authors.lastname: Shugart
authors.forename: R
authors.initials: R
authors.lastname: Balling
authors.forename: C T
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.forename: W G
authors.initials: WG
authors.lastname: Johnson
authors.forename: B C
authors.initials: BC
authors.lastname: Hamel
authors.forename: E C
authors.initials: EC
authors.lastname: Mariman
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005801:Genes, Homeobox / Q000235:genetics*; D005973:Glutamine / Q000235:genetics; D018398:Homeodomain Proteins; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D009436:Neural Tube Defects / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D016135:Spinal Dysraphism / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D005973:Glutamine; C068686:Pax3 protein, mouse; C070835:PAX1 transcription factor