Expression levels of Protocadherin-α transcripts are decreased by nonsense-mediated mRNA decay with frameshift mutations and by high DNA methylation in their promoter regions

The mouse protocadherin (Pcdh) clusters, Pcdh-α, -β, and -γ, are located on chromosome 18. Many polymorphic variations are found in the Pcdh-α genes in wild-derived and laboratory mouse strains. In comparing the expression levels of Pcdh-α isoforms among several strains, we observed lower expression levels of Pcdh-α9 in BLG2 and BFM/2, and of Pcdh-α8 in C57BL/6 (B6) than in the other strains. For Pcdh-α8, high DNA methylation (72.7%) in the promoter region was found only in B6, whereas 36.4-44.3% methylation was seen in the other strains. On the other hand, the Pcdh-α9 DNA-methylation levels were similar (23.6-36.3%) among the strains regardless of the difference in expression levels. Interestingly, however, the Pcdh-α9 variable exon in both BLG2 and BFM/2 included a premature termination codon (PTC) generated by a nucleotide deletion or insertion. Treatment with emetine, a potent inhibitor of nonsense-mediated mRNA decay (NMD), increased the expression level of Pcdh-α9 from the BLG2-Pcdh-α locus. These data indicate that the transcription levels of mature Pcdh-α mRNAs are decreased by the DNA-methylation state of the Pcdh-α promoter regions and by the NMD pathway during RNA maturation. And we correct some previous data on Sugino, H., Toyama, T., Taguchi, Y., Esumi, S., Miyazaki, M., Yagi, T., (2004) Negative and positive effects of an IAP-LTR on nearby Pcdaalpha gene expression in the central nervous system and neuroblastoma cell lines, Gene 337 91-103.