¹Zentrum für Humangenetik, Philipps-Universität Marburg, 35037 Marburg, Germany

²Institut für Medizinische Biometrie und Epidemiologie, Philipps-Universität Marburg, 35037 Marburg, Germany

³Kinderklinik der Universität Erlangen, 91054 Erlangen, Germany

⁴Kinderneurologisches Zentrum des Landes Rheinland-Pfalz, 55122 Mainz, Germany

Correspondence to: Manuela C Koch, Zentrum für Humangenetik, Bahnhofstrae 7, D-35037 Marburg, Germany; Tel: 06421/286 6269;Fax: 06421/286 8920; E-mail: koch2@mailer.uni-marburg.de

Neural tube defects (NTD) are among the most common congenital malformations in humans. The current view is that there are no major genes causing NTDs, but combinations of sequence variants in different genes have additive effects on determining the malformation. Therefore it is important to identify such sequence variants to get a better understanding of NTD pathogenesis. Studies on animal models have shown that BMP4 and NOG are involved in the patterning of the neural tube. We therefore performed a single-strand conformation analysis (SSCA) mutation screen for both genes in 179 spina bifida aperta (SBA) patients. Our SSCA screen revealed four missense mutations in BMP4 and one in NOG. It is likely that these mutations have acted together with other gene variants in independently segregating loci as susceptibility factors in these SBA cases. In addition, a case-control association study provides evidence for a genotype disequilibrium of BMP4 polymorphism 455TC (V152A) in exon 5. The frequency of the heterozygous 455TC genotype is lower in cases than in controls (nominal P=0.017), although allele frequencies are similar in both groups. A possible explanation for this finding might be that BMP4 455TC heterozygosity at this site is a protective factor in the normal population, although this hypothesis cannot be proven to date.

European Journal of Human Genetics (2002) 10, 753-756. doi:10.1038/sj.ejhg.5200875

neural tube defects; spina bifida aperta; BMP4; NOG