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Creutzfeldt\u2013Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt\u2013Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt\u2013Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt\u2013Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt\u2013Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, <jats:italic>PRNP<\/jats:italic>) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the <jats:italic>PRNP<\/jats:italic> gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt\u2013Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought. Copyright \u00a9 2012 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/rmv.725","type":"journal-article","created":{"date-parts":[[2012,2,28]],"date-time":"2012-02-28T13:29:41Z","timestamp":1330435781000},"page":"214-229","source":"Crossref","is-referenced-by-count":10,"title":["The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt\u2013Jakob disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Mark W.","family":"Head","sequence":"first","affiliation":[{"name":"The National CJD Research &amp; Surveillance Unit, School of Molecular &amp; Clinical Medicine University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Ironside","sequence":"additional","affiliation":[{"name":"The National CJD Research &amp; Surveillance Unit, School of Molecular &amp; Clinical Medicine University of Edinburgh  Edinburgh 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