Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects

Neural tube defects (NTDs), including anencephaly and spina bifida, are mul tifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom(1). Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor alpha -receptor (P dgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 th at have been associated with NTDs cause deregulated activation of the human PDGFRA promoter(2,5). There is an increasing awareness that genetic polymo rphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, o f which the two most abundant ones, designated H1 and H2 alpha, differ in a t least six polymorphic sites. In a transient transfection assay in human b one cells, the five haplotypes differ strongly in their ability to enhance reporter gene activity. In a group of patients with sporadic spina bifida, haplotypes with low transcriptional activity, including H1, were under-repr esented, whereas those with high transcriptional activity, including H2 alp ha, were over-represented. When testing for haplotype combinations, HI homo zygotes were fully absent from the group of sporadic patients, whereas H1/H 2 alpha heterozygotes were over-represented in the groups of both sporadic and familial spina bifida patients, but strongly underrepresented in unrela ted controls. Our data indicate that specific combinations of naturally occ urring PDGFRA promoter haplotypes strongly affect NTD genesis.