The Underlying Genetic Cause of Prion Diseases

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The human genome contains millions of base pairs that are successfully transcribed and translated to yield the gene products necessary for life. On occasion the protein products of translation face mutations that make them lethal to the human condition. In the past decade prion diseases have become more prominent in civilian life like mad cow disease in cattle, kuru in humans, and scrapie in sheep (Araújo, 2013). Prions are proteins that can have disastrous effects through mutation. The underlying genetic cause of prion diseases is under investigation to understand how polymorphisms, host factors and mutations in the prion protein gene (PRNP) lead to severe physiological impairments and ultimately death, exemplified by Creutzfeldt-Jakob Disease and Familial Fatal Insomnia (Capellari et al., 2011). In humans there are multiple phenotypes associated with prion diseases the most common of which are acquired Creutzfeldt-Jakob disease, inherited (also called familial) Creutzfeldt-Jakob disease, sporadic Creutzfeldt-Jakob disease and Familial Fatal Insomnia (Puoti et al., 2012). The gene PRNP encodes the normal prion protein specifically called prion protein cellular (PrPC) in humans (Capellari et al., 2011). Located on chromosome 20, the PRNP sequence is composed of two exons, which amount to a protein called PrPC of approximately 200-250 amino acids after post-translational modifications. One such modification is the addition of a glycosylphosphatidylinositol unit used as an attachment function, most-likely to attach to a neuron (Araújo, 2013). The PrPC has three domains, with the center being globular in nature composed of three alpha-helices and two beta-sheets with tertiary structure supporting the three dimensional shape... ... middle of paper ... ...e, R., Takahashi, Y., Song, C., Suzuki, A., Yamasaki, T., and Horiuchi, M. (2013). Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation. Journal of Virology, 87(24). Schmitz, M., Lüllmann, K., Zafar, S., Ebert, E., Wohlhage, M., Oikonomou, P., Schlomm, M., Mitrova, E., Beekes, M., and Zerr, I. (2013). Association of prion protein genotype and scrapie prion protein type with cellular prion protein charge isoform profiles in cerebrospinal fluid of humans with sporadic or familial prion diseases. Neurobiology of Aging, 1-12. Takeuchi, A., Kobayashi, A., Ironside, J., Mohri, S., & Kitamoto, T. (2013). Characterization of variant Creutzfeldt-Jakob Disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes. The Journal of Biological Chemistry, 288, 21659-21666.

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