PRNP A117V: research

What phenotype does it produce?

Chen and colleagues pooled the published GSS literature with 3 cases from their own unit, giving 329 cases with a female to male ratio of 1.13 to 1, median onset age 44 years and median duration 4 years. Of 294 cases they could categorise by clinical presentation, 50.7 percent were typical GSS, 24.8 percent CJD-like GSS and 16.3 percent GSS with dementia.

Clinical category varied significantly by genotype: P102L was more common in typical GSS, while A117V was prevalent in the CJD-like group. They report that codon 129 polymorphism had no effect on GSS phenotype overall, while the 129M allele acted as a protective factor among Asian patients.

A literature-pooled series carries the biases of what gets published, and category boundaries such as CJD-like GSS are defined by the authors rather than by a consensus criterion. The association is useful as a prior, not as a prediction for an individual: a person carrying A117V may present in any of these ways, and clinical interpretation belongs with their neurologist and genetics service.

What is the biochemical signature?

A117V shares the GSS pattern of an internal protease-resistant fragment rather than the C-terminal changes of CJD. Mercer and colleagues identified a 16 kDa thermolysin-resistant precursor of the 8 kDa proteinase K-resistant fragment, and found that signature in patients carrying P102L, A117V, H187R and F198S, with coordinates similar to the GSS stop codon mutations. Their conclusion is a shared GSS pathway distinct from that of CJD and scrapie.

The practical consequence is that a laboratory typing an A117V case with a standard proteinase K western blot optimised for CJD may see little, because the diagnostic fragment is small and generated under different conditions.

Why is antemortem testing unreliable?

Because the assay substrate matters more here than in classic sporadic disease. In the retrospective CSF panel reported by Myskiw and colleagues, the single A117V case was detected by end-point QuIC with the deer mouse recombinant substrate and missed by both the full-length hamster substrate and the truncated hamster substrate used in second-generation IQ-CSF RT-QuIC. The authors list GSS among the categories with particularly low sensitivity at international testing centres.

One case establishes nothing about sensitivity. It does mean that a negative CSF RT-QuIC in someone with a known A117V family history should not be read as excluding the disease, and that the substrate used is worth asking about.

What models exist?

A117V prions are now used as a reference human GSS inoculum. San-Juan-Ansoleaga and colleagues describe a method for generating prion disease models quickly by expressing modified prion proteins from AAV vectors in PrP-knockout mice, and report that mice challenged with mouse-adapted RML prions or with human GSS A117V disease-causing prions developed characteristic signs of prion disease. Their optimised construct used the human synapsin promoter with an MVM enhancer and WPRE element in the AAV9P31 serotype, with brain-wide expression at or above endogenous levels in some regions after intravenous administration.

This is a methods paper, and the relevance to A117V is that human GSS prions from this variant propagate in such a model, which gives a faster route to testing compounds against GSS material than building a transgenic line.

Related: the PRNP gene, penetrance, variants and codon 129.