Gene Type May Determine
Type Of CJD People Get

From Patricia Doyle, PhD
Genotype Of Recipient May Determine Type Of CJD That Develops Following BSE Infection
Medical Research Council
New research published by a team from the Medical Research Council (MRC) Prion Unit offers an explanation of why only people with a particular genetic make-up have so far developed variant Creutzfeldt-Jakob disease [abbreviated as CJD (new var.) or vCJD in ProMED-mail). It also provides evidence that other types of BSE (bovine spongiform encephalopathy)-derived prion infection with a different pattern of symptoms might occur in humans. The findings are published in the journal Science [Human Prion protein v129 prevent expression of vCJD phenotype - Science On line 11 Nov 2004].
Variant CJD (vCJD) is the human disease thought to be caused by eating food contaminated with the infectious agent, known as a prion, responsible for the epidemic of BSE or "mad cow disease" in cattle. So far, everyone known to have developed vCJD has been of a particular genetic type -- known as MM [methionine/methionine homozygotes]. Until now it has been a mystery why everyone that has developed vCJD is of the MM type, and one possibility is that they are simply the 1st to develop the disease when infected with BSE, and that people with the other genetic types1 (known as VV [valine/valine homozygotes] and MV [methionine/valine heterozygotes]) infected with BSE prions will also develop vCJD, but some years later.
In a series of experiments spanning more than 10 years, the MRC team has been studying [transgenic] mice genetically modified so that they make human prion proteins -- which are used to model human susceptibility to BSE. [The normal human prion protein is a membrane protein of unknown function. - Mod.CP] The team has now shown that mice with the human VV genetic type do become infected when given BSE or vCJD prions, but manifest a different form of the disease which looks quite different to vCJD and has a novel prion "strain" type.
Remarkably, when these novel prions were used to infect mice of the MM genetic type, the mice either developed a disease very like vCJD, or else a pattern of disease that looks like so-called sporadic CJD -- the "classical" form of CJD. This form has been known for many years, is seen all over the world and has not hitherto been associated with BSE. However, the new strain identified in the [transgenic] mice, being called "type 5'" has not yet been seen in people, and we do not know what pattern of disease it would cause. It could look like one of the forms of classical or sporadic CJD or perhaps be yet another different "variant" form.
The work from the MRC team suggests that type-4 prions, the type associated with vCJD, can only propagate themselves in people that make the M form of the protein. It seems the V form of the protein just cannot adopt the particular molecular shape that characterises type 4.
The studies in mice also suggest that if these prions were to pass from person to person (for example by blood transfusion) then, depending on the genetic type of the person becoming infected, at least 3 different patterns of disease might result: type 2 (which is seen in sporadic CJD); type 4 (which causes vCJD) or type 5 (which may cause a new pattern of disease).
Professor John Collinge, Director of the MRC Prion Unit, which is based at University College London, said: "These mouse studies give us vital clues about the behaviour of prions and how they appear to modify and adapt depending on the genetic makeup of the individual they are infecting. We always have to be cautious about making direct comparison to the human condition, but our work strongly suggests that we can not assume only those with one genetic profile are vulnerable to BSE infection. At this stage it is not possible to say how this should alter estimates of those likely to become ill, but our findings do suggest we should be taking steps to draw up a more sophisticated system of categorizing the disease so that we don't mistake BSE-related infection for a version of sporadic CJD."
* The human prion protein comes in 2 common forms, known as M and V. Because everyone has 2 copies of this gene, there are 3 possible genetic types: MM, MV and VV. Prions are rogue forms of one of the body's own proteins -- known as the prion protein -- which are misshapen. There are several different rogue or misshapen forms that can infect humans, and these different types of prions are known as "strains." This is analogous to different strains of other [infectious agents] such as [influenza] virus causing influenza or strains of salmonella causing different forms of food poisoning for example.
The strain of prion causing vCJD is known as type 4; types 1-3 cause the different forms of sporadic or classical CJD. Each strain causes a different pattern or type of disease. It is known that prion strains can change or "mutate" when they pass between different animals.
These transgenic mouse experiments have 2 significant implications for the human situation: (1) that novel types of prions may be generated during type 4 prion infection of humans insusceptible (V/V or V/M) to development of vJD; and (2) that these novel prions may have properties similar to the type 2 prion associated with sporadic CJD, or the type 5 prion of undefined potential. - Mod.CP
Patricia A. Doyle, PhD
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