PRNP Protective variants

What is the codon 219 change?

At position 219 in the prion protein gene most people carry glutamic acid, written E. A minority carry lysine, written K, and the change is usually written E219K. The 2024 review by Wang and colleagues collects the population data. The K allele occurs mainly in East Asia and the Pacific, with reported allele frequencies of about 3.5 to 9.4 percent in East Asian samples, 9.4 to 11.8 percent in Pacific populations and 10 to 19 percent in Melanesian samples. In the African, European, Latin American and South American samples in their tables the frequency is zero.

In East Asian sporadic Creutzfeldt-Jakob disease the K allele was absent or very rare, against roughly 4 to 6 percent in controls from the same populations. That contrast is the basis for calling the allele protective.

Three limits sit beside it. The authors state that the effect has so far been limited to East Asian populations, and that European datasets contain no K allele at all, so nothing can be tested there. Several of the contributing studies are small, and the authors call some of the findings too preliminary. And the protection is not absolute: two people in the United Kingdom with variant Creutzfeldt-Jakob disease carried the K allele, and the review describes the data in acquired disease as extremely limited.

The same change has a second meaning in transfusion medicine. People who carry lysine on both copies are negative for the KANNO blood group, and can form an antibody against it after pregnancy or transfusion. Reported cases had little clinical significance. If a report mentions KANNO, that is what is being described, and the blood service is the place to ask about it.

What about the variant found during the kuru epidemic?

Kuru was an acquired prion disease transmitted at mortuary feasts in the Eastern Highlands of Papua New Guinea. Mead and colleagues assessed more than 3,000 people from those populations, including 709 who had taken part in the feasts, of whom 152 later died of kuru. They found a change called G127V only in people from the region where kuru had been prevalent, in about half of the otherwise susceptible women from the highest-exposure area who carried methionine on both copies at codon 129. It was absent from kuru patients and from unexposed populations worldwide. The authors read it as a resistance factor that was selected during the epidemic.

This finding carries weight in laboratory research, because it points to a single position in the protein where a change blocks the disease process. It has no application to a family outside that region, where the allele has not been found.

Does codon 129 count as protective?

Partly, and only in a statistical sense. Codon 129 can carry methionine or valine, and most people have one of three genotypes: MM, MV or VV. Carrying one of each, written MV, is associated with lower risk in the acquired forms of the disease, and the kuru survivors who had been exposed were mostly MV.

In genetic prion disease codon 129 does something different. Goldman and Vallabh describe it as influencing how long the illness lasts in some variants, and as influencing risk in sporadic and iatrogenic disease, while not appearing to influence age at onset for the commonest genotypes. For D178N the codon 129 allele sitting on the same copy of the gene as the variant decides which named syndrome follows. None of that makes a codon 129 genotype a protective result in the way families hope.

Can a protective allele cancel out a pathogenic variant?

Nothing in the published work supports planning on that. Reports in Japanese patients describe people who carried lysine at codon 219 alongside a pathogenic variant and whose symptoms were described as milder or more prolonged, but these are observations on small numbers of patients rather than effect estimates, and they are reports of people who became ill.

Two things follow for a family. A pathogenic variant with a protective allele beside it is still a pathogenic variant, and the counselling conversation does not change. And a protective allele found on its own, in someone with no pathogenic variant, is not a health finding to act on, because nothing is done differently for anyone on the strength of it.

Is any of this a test I can ask for?

No clinical service offers these alleles as a risk test. They appear on a report because the laboratory sequenced the region or genotyped the polymorphism as part of its standard work, not because the result guides care. Wang and colleagues note that no validated noninvasive diagnostic or therapeutic approach exists for human prion disease outside research, and their suggestions about using the KANNO antibody are proposals for future experiments.

Anyone holding a report that mentions codon 219, codon 127 or codon 129 can ask the issuing laboratory what it measured, and a genetic counsellor what it means in their family. Counselling comes first describes those appointments, and this page cannot interpret an individual result.

Where the evidence is thin

The codon 219 association rests mainly on case control comparisons in East Asian populations, some of them small, with no comparable data from populations where the allele does not occur. The kuru variant rests on one epidemic in one region. The codon 129 effect is a shift in risk across groups of people, not a property of any one person. Future work that changes any of these conclusions will be in the same places: larger cohorts, and populations that have not yet been studied.

Neighbouring pages are the variants hub, P105L and V180I, which is also concentrated in East Asia.