PRNP Protective variants: research

How strong is the codon 219 evidence?

Shibuya and colleagues (Annals of Neurology 1998) examined 85 Japanese sporadic CJD patients for the codon 219 polymorphism, which has an allele frequency of about 6 percent in the general Japanese population. No Glu/Lys heterozygote was found among the 85. Four of 43 patients with non-CJD dementia carried the heterozygous genotype, at a frequency similar to the general population. The authors proposed that the heterozygous genotype may be uniquely absent in sporadic CJD.

Wang and colleagues (Frontiers in Neurology 2024) collect the population data. Reported Glu/Lys genotype frequencies in general populations are 12.0 to 14.4 percent in Japanese, 7.82 to 8.76 percent in South Korean and 2.2 to 15.8 percent in Chinese samples, with Lys/Lys at 0 to about 0.9 percent. Serbian and Italian samples in their table show 100 percent Glu/Glu. In East Asian sporadic CJD cohorts the Lys allele was absent or very rare, 0 to 0.53 percent, against about 4 to 6 percent in controls. In Japanese genetic CJD the Lys allele frequency was 0 to 1.3 percent and heterozygote frequency 0 to 2.2 percent, significantly lower than in controls.

Two limits follow directly from those numbers. The authors state that the protective effect of E219K heterozygosity against sporadic CJD has so far been limited to East Asian populations, and that European datasets contain no Lys allele at all, so no correlation can be assessed there. They also note that many of the contributing studies are small and that the findings need validation in larger and non-Asian cohorts. Their review further reports heterozygotes with variant CJD in the United Kingdom, and reports suggesting heterozygosity did not confer resistance in acquired disease.

Reported interactions with pathogenic variants in Japanese patients, in the same review, are that E219K alongside E200K prolonged mild symptoms and that Lys at 219 on the P102L allele appeared to ease symptoms in some patients. These are observations on small numbers of patients, not effect estimates.

What does G127V show?

Mead and colleagues (New England Journal of Medicine 2009) assessed more than 3,000 people from Eastern Highland populations in Papua New Guinea, including 709 who had taken part in mortuary feasts, of whom 152 later died of kuru. They reported a PRNP variant, G127V, found only in people from the region where kuru had been prevalent. It was present in about half of otherwise susceptible women from the highest-exposure area who were homozygous for methionine at codon 129. It was not found in kuru patients, or in unexposed population groups worldwide. Families carrying the allele had a significantly lower incidence of kuru than geographically matched control families. The authors read G127V as an acquired resistance factor selected during the epidemic rather than a cause of it.

Asante and colleagues (Nature 2015) tested the allele in transgenic mice. Mice expressing both variant and wild-type human PrP were completely resistant to kuru and classical CJD prions, and could still be infected with variant CJD prions. Mice expressing only PrP V127 were completely resistant to all strains tested. Experiments across different ratios of variant to wild-type PrP showed a dose-dependent inhibition of wild-type prion propagation. The authors conclude that V127 is completely refractory to prion conversion, that it acts by a different mechanism from the codon 129 polymorphism, and that this single substitution at a residue invariant across vertebrate evolution is as protective as deleting the protein.

The strain-specific gap limits interpretation. Resistance in those experiments was complete for kuru and classical CJD prions in mice carrying both alleles and incomplete for variant CJD prions.

Where does codon 129 fit?

Appleby and colleagues (Frontiers in Neurology 2022) describe kuru as having selected for the 129 valine allele, the more resistant genotype, in Papua New Guinea during the period when mortuary feasting was practised. In the 2009 kuru study, exposed survivors were predominantly heterozygous at codon 129. Codon 129 heterozygosity is therefore best treated as a resistance factor of partial effect, in contrast to the all-or-none results reported for V127 in mice. Haplotype and duration effects at codon 129 are on codon 129.

Appleby and colleagues also describe the codon 219 polymorphism as strongly protective for sporadic CJD, occurring only in East and South Asian populations at roughly 14 percent of the general Japanese population and 8 percent of the Korean population, with heterozygosity seen in under 1 percent of sporadic CJD cases but more commonly in acquired prion diseases.

Does losing one copy of PRNP protect?

Minikel and colleagues (Science Translational Medicine 2016) found heterozygous N-terminal truncating PRNP variants, at residue 131 or earlier, in four ExAC individuals. Three were validated, and those three were free of overt neurological disease at ages 79, 73 and 52, with no reported personal or family history of neurodegeneration or peripheral neuropathy. Heterozygous C-terminal truncating variants, at residue 145 or later, are known to cause prion disease. That contrast is the human genetic basis most often cited for lowering PrP as a therapeutic strategy, covered in PrP lowering. Three individuals is a small observation, and the authors present it as such.

What these findings do not support

None of these alleles is used as a clinical test, and none of the studies above was designed to give an individual risk estimate. The codon 219 and codon 127 associations rest on specific populations, and the codon 127 work rests on one epidemic and a transgenic mouse model. Interpretation of a particular person’s PRNP result belongs with a genetic counsellor and the reporting laboratory. The plain-language version of this page is protective variants explained, and the neighbouring low-penetrance variants are V180I and P105L.