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Title: Prevalence of the prion gene E211K variant in U.S. cattle

item Heaton, Michael - Mike
item Keele, John
item Harhay, Gregory
item Richt, Juergen
item Koohmaraie, Mohammad
item Wheeler, Tommy
item Shackelford, Steven
item Casas, Eduardo
item King, David - Andy
item Sonstegard, Tad
item Van Tassell, Curtis - Curt
item Chase, Chadwick - Chad
item Smith, Timothy - Tim
item Clawson, Michael - Mike

Submitted to: BioMed Central (BMC) Veterinary Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/14/2008
Publication Date: 7/14/2008
Citation: Heaton, M.P., Keele, J.W., Harhay, G.P., Richt, J., Koohmaraie, M., Wheeler, T.L., Shackelford, S.D., Casas, E., King, D.A., Sonstegard, T.S., Van Tassell, C.P., Neibergs, H.L., Chase, C.C., Kalbfleisch, T.S., Smith, T.P., Clawson, M.L., Laegreid, W.W. 2008. Prevalence of the prion gene E211K variant in U.S. cattle. BioMed Central (BMC) Veterinary Research [journal online]. 4:25. Available: (

Interpretive Summary: Classical bovine spongiform encephalopathy (BSE) is a transmissible fatal brain-wasting disease in cattle. Also known as "mad cow disease," it was first diagnosed in 1986, in the United Kingdom (UK). BSE has since been found in 24 countries including Japan, Canada, and the United States. Consumption of contaminated beef from BSE-affected animals in the UK has been implicated as the most likely cause of a similar disease in humans, variant Creutzfeldt-Jakob Disease (vCJD). However, after regulations were put in place to prevent BSE-contaminated tissues from entering the feed supply and active BSE surveillance was increased, the number of BSE cases dropped dramatically. This was followed by a corresponding reduction in human vCJD cases. A rare type of BSE in cattle, referred to as “atypical BSE,” has recently been identified and is of interest because it develops in older animals without apparent exposure to other BSE-contaminated material. Although only 30 atypical BSE cases have been identified worldwide, they are significant because of their possible link to other CJDs in humans (i.e., other than vCJD). In 2006, a U.S. case of atypical BSE was discovered in Alabama and later reported to have a mutation (E211K) in the bovine gene required for BSE (i.e., the prion gene). This bovine mutation is strikingly similar to the most commonly inherited defect in humans that causes a type of CJD to develop late in life. This may imply that older cattle with the E211K mutation may also develop atypical BSE late in life. To determine whether this DNA mutation is rare in U.S. cattle, an accurate test was developed and more than 6062 cattle from all parts of the beef and dairy industry were tested for the presence of the mutation. This represents the first prevalence estimate of a mutation that may cause atypical BSE in older animals without prior exposure to BSE-contaminated tissues. None of the cattle tested were found to have the E211K mutation. Thus, the mutation appears to be either exceedingly rare or non-existent among U.S. purebred, crossbred, beef, and dairy cattle.

Technical Abstract: Background: In 2006, an atypical U.S. case of bovine spongiform encephalopathy (BSE) was discovered in Alabama and later reported to be polymorphic for glutamate (E) and lysine (K) codons at position 211 in the bovine prion protein gene (Prnp) coding sequence. A bovine E211K mutation is important because it is analogous to the most common pathogenic mutation in humans (E200K) which causes hereditary Creutzfeldt–Jakob disease, an autosomal dominant form of prion disease. The present report describes a high-throughput matrix-associated laser desorption/ionization-time-of-flight mass spectrometry assay for scoring the Prnp E211K variant and its use to determine an upper limit for the K211 allele frequency in U.S. cattle. Results: The K211 allele was not detected in 6062 cattle, including those from five commercial beef processing plants (3892 carcasses) and 2170 registered cattle from 42 breeds. Multiple nearby polymorphisms in Prnp coding sequence of 1456 diverse purebred cattle (42 breeds) did not interfere with scoring E211 or K211 alleles. Based on these results, the upper bounds for prevalence of the E211K variant was estimated to be extremely low, less than 1 in 2000 cattle (Bayesian analysis based on 95% quantile of the posterior distribution with a uniform prior). Conclusion: No groups or breeds of U.S. cattle are presently known to harbor the Prnp K211 allele. Because a carrier was not detected, the number of additional atypical BSE cases with K211 will also be vanishingly low.