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 PAXI, 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 PAXI, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAXI 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 PAXI suggests that, in principle, this gene can act as a risk factor for human NTD. (JMed Genet 1996;33:655-660)

Determination of Methyl Tetrahydrofolate Reductase, TEAD2 and PAX3 Gene Polymorphisms in Patients with Spina Bifida

“…PAX3 eksikliği olan farelerde spina bifida oluştuğu ve başka birçok nöral krest anomalilerinin ortaya çıktığı gösterilmiştir (1,5,26) . Literatürde NTD hastalarında PAX3 polimorfizmlerinin araştırıl-dığı çalışma sayısı oldukça sınırlıyken TEAD2 gen polimorfizmlerin incelendiği çalışmaya rastlanmamıştır (9,31) . Çalışmamızda TEAD2 genotipleri ve allel sıklıkları açısından hasta ve kontrol grupları arasında anlamlı bir fark görülmemiştir.…”

Mutations in PAX1 may be associated with Klippel–Feil syndrome

“…30 To support this hypothesis, a missense mutation in a conserved region of the PAX1 paired box has been described in a foetus with a neural tube defect. 31 The mutation Q42H (Q115H in our sequence) was inherited through an unaffected mother and grandmother. A phenotype reminiscent of extreme spina bifida occulta in humans is also seen in mice doubly mutant for undulated and Patch.…”

Future Nutrigenetics: In Search of the Missing Genetic Variation

“…This is also revealed by functional assays performed for 2 of the 6 mutations. For the PAX1 mutation it could be demonstrated that it diminished the affinity of the protein for binding to its target DNA sequences [17,33] . One of the VANGL1 mutations was shown to abolish the complexation with its normal binding partners.…”