Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs)

Abstract

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 455T?C (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.

Gene expression profile activated by the chemokine CCL5/RANTES in human neuronal cells

“…Moreover, BMP4 treatment promoted postnatal differentiation of cerebellar neurons (Angley et al, 2003). Studies on animal models have shown that BMP4 is involved in the patterning of the neural tube; missense mutations in BMP4 were found in spina bifida aperta patients (Felder et al, 2002). The increased expression of PIGS, KLF7, and BMP4 was confirmed by real‐time RT‐PCR experiments and was induced selectively by CCL5 but not by CXCL12 treatment.…”

Multiligand Endocytosis and Congenital Defects: Roles of Cubilin, Megalin and Amnionless

“…The interaction of these factors may determine the incidence and severity of the CNS malformations. Mutations in genes involved in dorso-ventral patterning of the NT like BMP-4, Nog, Pax3, Six3 or Shh are known to be associated with various NT malformations in humans [5][6][7][8][9]. Reported environmental causes include physical agents, therapeutic drugs, chemicals or infectious agents [4,10].…”

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

“…In rare cases, syndromes that variably present with NTDs have been associated with a mutation in a single gene (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Using traditional linkage disequilibrium, patient studies of individual (non-folate-related) candidate genes, including jumonji (JMJ) (37), apolipoprotein E (ApoE), apolipoprotein B (ApoB) (38), bone morphogenetic protein-4 (BMP4) (39), CITED2 (40), transcription factor AP2 (TFAP2) (41), multiple sequence homeobox-2 (MSX2) (41), PAX3 (42) and noggin (NOG) (43), have only rarely succeeded in ascribing attributable risk for NTDs to specific genes.…”