Codon 129

How large is the genotype effect on risk?

Jones and colleagues ran a two-stage genome-wide association study in European ancestry populations using samples from 5208 sporadic CJD cases collected between 1990 and 2014, with country-matched public control data. Three loci reached genome-wide significance and replicated: PRNP (rs1799990, additive model odds ratio 1.23, 95 percent CI 1.17 to 1.30, p equal to 2.68 times 10 to the minus 15; heterozygous model p equal to 1.01 times 10 to the minus 135), STX6 (rs3747957, odds ratio 1.16, 1.10 to 1.22) and GAL3ST1 (rs2267161, odds ratio 1.18, 1.12 to 1.25).

The contrast between the two PRNP models is the finding. rs1799990 is the codon 129 polymorphism, and the enormous heterozygous-model statistic against a modest additive odds ratio shows that the effect is not a dose effect of one allele but a protective effect of carrying both. The follow-up analyses in that paper attribute the PRNP and GAL3ST1 associations to common variation of this kind.

The same locus dominates acquired disease. In the variant CJD genome-wide association study, PRNP was strongly associated across markers and across all categories of prion disease, with the best single SNP association in variant CJD at p equal to 2.5 times 10 to the minus 17 and the best haplotypic association at p equal to 1 times 10 to the minus 24, and the authors report that a further nearby SNP conferred increased variant CJD risk in addition to codon 129 itself.

Heterozygote advantage is not a statistical artefact of European cohorts. In the kuru-exposed population of Papua New Guinea, survivors of the epidemic were predominantly codon 129 heterozygotes, which is the population genetic signature of the same effect under an epidemic exposure.

How does it shape the phenotype?

In sporadic disease, codon 129 genotype combined with the PrPSc type gives the subtype classification. In the 300-case series, the classic phenotype carried type 1 protein with at least one methionine allele, the ataxic and kuru-plaque variants carried type 2 with valine homozygosity or heterozygosity, and the thalamic and cortical type 2 phenotypes occurred in methionine homozygotes. The subtype pages are linked from sporadic CJD subtypes.

In inherited disease the polymorphism acts on the same chromosome as the mutation. D178N with methionine in cis gives fatal familial insomnia and with valine in cis gives a genetic CJD subtype, established in 30 affected people across eleven kindreds. The parallel finding in the genetic CJD classification series is that PrPSc type and the codon 129 allele on the mutated allele, rather than the identity of the mutation, define six phenotype groups that largely reproduce the sporadic subtypes. See D178N and penetrance.

Why does it are important for laboratory assays?

Because the substrate is a prion protein with a codon 129 residue of its own, and seeding depends on the match. Belondrade and colleagues amplified PrPTSE from 14 sporadic CJD brains in three substrates, two from transgenic mice expressing human PrP with either methionine or valine at position 129 and one from bank voles. Amplification was strongly seed and substrate dependent. Valine 129 substrate was more permissive than methionine 129 substrate for sporadic prions, and amplification in a mismatched human substrate shifted the molecular PrPTSE type during the reaction, while bank vole substrate propagated all subtypes with the original type preserved.

Two consequences follow for anyone reading assay results. A negative amplification result can reflect substrate mismatch rather than absence of seeds, and a molecular type reported after amplification in a mismatched substrate may not be the type the patient’s brain carried.

What this page does not say

Nothing here can be applied to an individual. Codon 129 genotype is common variation with a population-level effect on susceptibility, it does not predict whether any person will develop prion disease, and it is not a predictive test. Genetic counselling comes first in any decision about testing, and choosing not to test is a valid choice: see counselling comes first and the right not to know.

Related: genetics hub, penetrance, the PRNP gene and variants.