PRNP is the single gene in which variation is established to cause human prion disease. This page covers the gene itself. Individual variants are at variants, the common polymorphism at codon 129, and risk estimation at penetrance.
What is the structure of the gene?
Puckett and colleagues determined it in 1991. The gene lies on the short arm of chromosome 20, in a region that then had few known genes or markers, and has the same simple structure as the hamster gene: two exons and a single intron. Unlike the hamster gene, the human gene appears to have a single major transcriptional start site, and the region immediately 5 prime of that site is GC-rich in the manner typical of housekeeping genes.
Two details from that paper still are important for diagnostics. The coding region includes five octameric peptide repeats predicted to form a beta-pleated sheet, and the genomic clone the authors isolated carried a 24 base pair deletion removing one of them. Repeat number variation is therefore part of the normal and the pathogenic range, which is why insertions and deletions in this region need care to interpret; see octapeptide repeat insertions.
The simplicity of the structure also explains the standard clinical test. Because the whole open reading frame sits in one exon, bidirectional Sanger sequencing of that coding region is a complete analysis of coding variation, which is what most laboratories offer.
What classes of variant are described?
Appleby and colleagues set out the clinical framework. PRNP encodes the cellular prion protein, which is the biological substrate for both transmission and neurotoxicity. Human prion disease has three causes, sporadic, genetic and acquired, and PRNP polymorphisms and pathogenic variants affect the frequency, age at onset and clinicopathological phenotype of all of them. Their review covers what is needed for clinical care, predictive testing and genetic counselling, and notes that because the prion protein is required for transmission and neurotoxicity, treatments targeting its production are under investigation for all forms of the disease, including asymptomatic carriers.
What that framework does not include is a regulatory-variant category. Lian and colleagues sequenced PRNP non-coding regions alongside exomes in 67 VPSPr cases and found no causal variant, with upstream expression quantitative trait loci showing no independent association. No established non-coding PRNP cause of human prion disease appears in the sources read here.
Why does the loss of function evidence matter?
Because it is the safety argument for every programme that aims to reduce prion protein. Minikel and colleagues reported that truncating variants in PRNP have position-dependent effects, and that true loss-of-function alleles were found in healthy older individuals, which they state supports the safety of therapeutic suppression of prion protein expression.
The animal evidence then addresses how much suppression is needed and when. Minikel and colleagues tested antisense oligonucleotide-mediated PrP suppression across dose, regimen, prion strain and treatment timepoint in intracerebrally infected mice. Less than 25 percent PrP suppression was sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rises in neuroinflammation and neuronal injury markers were reversed by a single dose given after pathological change was detected. Chronic suppression begun at any point up to early neuropathology conferred benefit comparable to constitutive heterozygous PrP knockout, and even after frank symptoms including weight loss, a single treatment prolonged survival by months in a subset of animals.
These are mouse experiments with intracerebral inoculation of laboratory strains, and benefit measured largely as survival time. They support the therapeutic hypothesis; they do not establish benefit in people. The clinical programmes built on it are described at therapeutics research and PrP lowering.
What the gene does not tell you
A PRNP result cannot be interpreted outside a genetics service, and the variant classifications in public databases have been wrong often enough that the penetrance literature exists to correct them. Anyone weighing a test should start with genetic counselling, and declining testing is a valid choice: see counselling comes first and predictive testing.
Related: genetics hub, codon 129, penetrance and variants.
Sources for this page
- Puckett C, Concannon P, Casey C, Hood L (1991) Genomic structure of the human prion protein gene, Am J Hum Genet 49(2):320-329
- Appleby BS, Shetty S, Elkasaby M (2022) Genetic aspects of human prion diseases, Front Neurol 13:1003056
- Minikel EV and others (2016) Quantifying prion disease penetrance using large population control cohorts, Sci Transl Med 8(322):322ra9
- Minikel EV and others (2020) Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints, Nucleic Acids Res 48(19):10615-10631
- Lian Y and others (2025) Search for a genetic cause of variably protease-sensitive prionopathy, PLoS Pathog 21(8):e1013384