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Background  Secreted phosphoprotein 1 (SPP1 or Osteopontin, OPN) is a multifunctional matricellular glycoprotein involved in development and regeneration of skeletal muscle. Previously, we have demonstrated that porcine  SPP1  shows breed-related differential mRNA expression during myogenesis. With the aim to identify putative contributing  cis -regulatory DNA variation we resequenced the 5' upstream region of the gene in the respective breeds Pietrain and Duroc. We found two single nucleotide polymorphisms (SNP; [GenBank: M84121 ]: g.1804C>T and g.3836A>G). We focused our investigation on the SNP g.3836A>G, because  in silico  analysis and knowledge about the regulation of  SPP1  suggested an effect of this SNP on a CCAAT/enhancer binding protein beta (C/EBPβ) responsive transcriptional enhancer.    Results  Using electrophoretic mobility shift assay we demonstrated that, similar to human  SPP1 , the 3' terminal end of the first intron of porcine  SPP1  harbors a C/EBPβ binding site and showed that this binding site is negatively affected by the mutant G allele. Genotyping of 48 fetuses per breed revealed that the G allele segregated exclusively in Duroc fetuses with a frequency of 57 percent. Using real-time quantitative PCR we showed that, consistent with its negative effect on a transcriptional enhancer element, the G allele tends to decrease mRNA abundance of  SPP1  in the fetal  musculus longissimus dorsi  (~1.3 fold; P ≥ 0.1).  Moreover, we showed that the SNP g.3836A>G leads to ubiquitous aberrant splicing of the first intron by generating a  de novo  and activating a cryptic splice acceptor site. Aberrantly spliced transcripts comprise about half of the  SPP1  messages expressed by the G allele. Both aberrant splice variants differ from the native transcript by insertions in the leader sequences which do not change the reading frame of  SPP1 .    Conclusion  At the 3' terminal end of the first intron of the porcine  SPP1  we identified a unique, dually functional SNP g.3836A>G. This SNP affects the function of the  SPP1  gene at the DNA level by affecting a C/EBPβ binding site and at the RNA level by activating aberrant splicing of the first intron, and thus represents an interesting DNA-marker to study phenotypic effects of  SPP1  DNA-variation.

bmc molecular biology

Dual effect of a single nucleotide polymorphism in the first intron of the porcine Secreted phosphoprotein 1 gene: allele-specific binding of C/EBP beta and activation of aberrant splicing