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Background  Presenilin proteins are part of a complex of proteins that can cleave many type I transmembrane proteins, including Notch Receptors and the Amyloid Precursor Protein, in the middle of the transmembrane domain. Dominant mutations in the human presenilin genes PS1 and PS2 lead to Familial Alzheimer's disease. Mutations in the  Caenorhabditis elegans sel-12  presenilin gene cause a highly penetrant egg-laying defect due to reduction of signalling through the  lin-12 /Notch receptor. Mutations in six  spr  genes (for  s uppressor of  pr esenilin) are known to strongly suppress  sel-12 . Mutations in most strong  spr  genes suppress  sel-12  by de-repressing the transcription of the largely functionally equivalent  hop-1  presenilin gene. However, how mutations in the  spr-2  gene suppress  sel-12  is unknown.    Results  We show that  spr-2  mutations increase the levels of  sel-12  transcripts with Premature translation Termination Codons (PTCs) in embryos and L1 larvae. mRNA transcripts from  sel-12  alleles with PTCs undergo degradation by a process known as Nonsense Mediated Decay (NMD). However,  spr-2  mutations do not appear to affect NMD. Mutations in the  smg  genes, which are required for NMD, can restore  sel-12(PTC)  transcript levels and ameliorate the phenotype of  sel-12  mutants with amber PTCs. However, the phenotypic suppression of  sel-12  by  smg  genes is nowhere near as strong as the effect of previously characterized  spr  mutations including  spr-2 . Consistent with this, we have identified only two mutations in  smg  genes among the more than 100  spr  mutations recovered in genetic screens.    Conclusion   spr-2  mutations do not suppress  sel-12  by affecting NMD of  sel-12(PTC)  transcripts and appear to have a novel mechanism of suppression. The fact that mutations in  smg  genes can ameliorate the phenotype of  sel-12  alleles with amber PTCs suggests that some read-through of  sel-12(amber)  alleles occurs in  smg  backgrounds.

Mutations in genes involved in nonsense mediated decay ameliorate the phenotype of sel-12 mutants with amber stop mutations in Caenorhabditis elegans