A Polymorphism in a Conserved Posttranscriptional Regulatory Motif Alters Bone Morphogenetic Protein 2 (BMP2) RNA:Protein Interactions

Abstract

The bone morphogenetic protein (BMP)2 gene has been genetically linked to osteoporosis and osteoarthritis. We have shown that the 3'-untranslated regions (UTR) of BMP2 genes from mammals to fishes are extraordinarily conserved. This indicates that the BMP2 3'-UTR is under stringent selective pressure. We present evidence that the conserved region is a strong posttranscriptional regulator of BMP2 expression. Polymorphisms in cis-regulatory elements have been proven to influence susceptibility to a growing number of diseases. A common single nucleotide polymorphism (SNP) disrupts a putative posttranscriptional regulatory motif, an AU-rich element, within the BMP2 3'-UTR. The affinity of specific proteins for the rs15705 SNP sequence differs from their affinity for the normal human sequence. More importantly, the in vitro decay rate of RNAs with the SNP is higher than that of RNAs with the normal sequence. Such changes in mRNA:protein interactions may influence the posttranscriptional mechanisms that control BMP2 gene expression. The consequent alterations in BMP2 protein levels may influence the development or physiology of bone or other BMP2-influenced tissues.

Modulation of Bone Morphogenetic Protein (BMP) 2 gene expression by Sp1 transcription factors

“…Because BMP2 is such a potent growth factor, many mechanisms have evolved to precisely regulated expression and function. Indeed, the mammalian BMP2 promoter and 3′ untranslated regions are functionally conserved between four orders of mammals (Abrams et al, 2004;Fritz et al, 2004Fritz et al, , 2006. Negative regulation of BMP2 expression and function is a common theme.…”

A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants

“…In addition, two recently published and functionally characterised USS variants in the BMP2 (Fritz et al 2006) and SEPN1 (Allamand et al 2006) genes were also included for analysis (Table 1; see Supplementary Tables S1-S5 for sequence details). Although the general principles involved in analysing the 3¢ RR variants have been previously described , it is nevertheless important to explain how the USS variants were sub-divided into the five groups listed in Table 1.…”

“…Variations in the BMP2 gene (MIM# 112261; encoding bone morphogenetic protein 2) have been associated with both osteoporosis (Styrkarsdottir et al 2003) and osteoarthritis (Valdes et al 2004). A common A>C SNP in BMP2, located within the AUrich USS, was found to be functional: the minor C allele not only has a different affinity for specific proteins but also exhibits a higher in vitro decay rate as compared with the major A allele (Fritz et al 2006). Unlike the above-mentioned pattern 0 and pattern I variants, the A>C SNP in the BMP2 gene was located within a hairpin loop (here termed pattern II; Fig.…”

Species-specific cis-Regulatory Elements in the 3′-Untranslated Region Direct Alternative Polyadenylation of Bone Morphogenetic Protein 2 mRNA

“…Alternative polyadenylation leading to mRNAs with distinct 3Ј-UTRs, along with usage of distinct promoters (48,49) and other regulatory mechanisms (15,17,18,50,51), are important pieces of the mechanisms that precisely regulate the temporal and spatial patterns of BMP2 synthesis.…”