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Title: Frequent Missense and Insertion/Deletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP

Author
item DAUDE, NATHALIE - University Of Alberta
item WOHLGEMUTH, SERENE - University Of Alberta
item ROGAEVA, EKATERINA - University Of Toronto
item FARID, A - Nova Scotia Agricultural College
item Heaton, Michael - Mike
item WESTAWAY, DAVID - University Of Alberta

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/15/2009
Publication Date: 8/6/2009
Citation: Daude, N., Wohlgemuth, S., Rogaeva, E., Farid, A.H., Heaton, M.P., Westaway, D. 2009. Frequent Missense and Insertion/Deletion Polymorphisms in the Ovine Shadoo Gene Parallel Species-Specific Variation in PrP. PLoS One [serial online]. 4(8):e6538.

Interpretive Summary: Prion diseases are a group of fatal brain-wasting diseases in humans and animals. They may be transmitted from one individual to another, or these diseases may also develop without apparent contact of an infected source. The prion gene and its encoded prion protein have long been known to play a central role in prion diseases. Among other factors, natural variation in the prion gene has been associated with disease susceptibility. Recently, a second gene and its protein (shadoo) have also been implicated in prion disease. The present study examined the natural genetic variation in shadoo genes from humans and the model organisms mice and sheep. Shadoo from human and mouse populations showed relatively little genetic diversity compared to sheep. However, sheep populations harbored a number of different versions of the shadoo gene that were predicted to encode significantly different shadoo proteins. This raises the possibility that, like the prion gene, genetic variation in shadoo may influence prion disease. Shadoo expression has been linked to mouse and human prion diseases, thus, investigating shadoo will shed light onto prion diseases and their potential prevention and cure.

Technical Abstract: Background: The cellular prion protein PrP**C is encoded by the Prnp gene. This protein is expressed in the central nervous system (CNS) and serves as a precursor to the misfolded PrP**S**c isoform in prion diseases. The prototype prion disease is scrapie in sheep, and, whereas, Prnp exhibits common missense polymorphisms for V136A, R154H and Q171R in ovine populations, genetic variation in mouse Prnp is limited. Recently, the CNS glycoprotein Shadoo (Sho) has been shown to resemble PrP**C, both in a central hydrophobic domain and in activity in a toxicity assay performed in cerebellar neurons. Sho protein levels are reduced in prion infections in rodents. Prompted by these properties of the Sho protein, we investigated the extent of natural variation in SPRN. Principal Findings: Paralleling the case for ovine versus human and murine PRNP, we failed to detect significant coding polymorphisms that alter the mature Sho protein in a sample of neurologically normal humans, or in diverse strains of mice. However, ovine SPRN exhibited four missence mutations and expansion/contraction in a series of five tandem Ala/Gly-containing repeats R1-R5 encoding Sho's hydrophobic domain. A Val71Ala polymorphism and polymorphic expansion of wt 67(Ala)3Gly70 to 67(Ala)5Gly72 reached frequencies of 20%, with other alleles including delta67-70 and a 67(Ala)6Gly73 expansion. Sheep V71, A71, delta67-70 and 67(Ala)6Gly73 SPRN alleles encoded proteins with similar stability and posttranslational processing in transfected neuroblastoma cells. Significance: Frequent coding polymorphisms are a hallmark of the sheep PRNP gene, and our data indicate a similar situation applies to ovine SPRN. Whether a common selection pressure balances diversity at both loci remains to be established.