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Prion Protein Mutation Database

PrP Gene Structure

The PrP gene, PRNP (NC_000020.11 genomic coordinates: 4699221 – 4699982), has been localised to the short arm of chromosome 20 (20pter-12)1-2PRNP is a single-copy 16 Kb gene and contains two exons, separated by a 13 Kb intron. Exon 1 is non-coding and is thought to comprise the transcriptional initiation site. The open reading frame (ORF), encoding the PrP protein, is composed of 253 amino acids and located entirely within exon 2 (Figure 1)3. The 5’ region of the PrP gene does not contain a canonical TATA box, is very GC rich (83% GC residues), and has numerous GC repeats. The six base-pair sequence CCGCCC is repeated four times in exon 1; such GC-rich features are commonly seen in housekeeping genes3-4.

Figure 1: Nucleotide bases 1-762 of the PRNP coding sequence in exon 2, corresponding to bases 4699221 to 4699982 of Chromosome 20, GRCh38.P13 (NC_000020.11). The conceptual amino-acid translation of the 253 residue protein is shown below, with reference numbering given to the left. Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon.  

The human PRNP gene locus contains three genes: PRNPPRND and a novel gene, PRNT (Figure 2).  PRND is a single-copy gene located 27 Kb downstream of PRNP and is also composed of a two-exon structure. A further 3 Kb downstream of PRND, is the PRNT gene5. Whereas PRND is paralogous to PRNPPRNT exhibits no detectable sequence homology with any of the three members comprising the prion gene family, and is thought to be unlikely to be a protein-coding gene, but rather, may represent a region of mRNA-like long non-coding RNA6 (Figure 2).

In addition to PRNP, the other members of this gene family include the also neuropathologically relevant paralogs PRND (doppel protein, chromosome 20), expressed in testis and SPRN (shadoo, or shadow of prion protein, chromosome 10), expressed mainly in brain5,7-8. These three loci likely derived by retroposition of an ancestral ZIP metal ion transporter gene9. PrP is found in most adult tissue, with the highest levels of expressed protein in the central nervous system, particularly in association with synaptic membranes8.

Figure 2: Schematic representation of human prion gene family members. PRNPPRND and PRNT are clustered on the same genomic locus on chromosome 20. The distance between PRNPPRND and PRNT is given in kilobases (Kb). SPRN is also composed of a two-exon structure and is located on chromosome 10 in man. For each gene, the open reading frame (ORF) is indicated on the relevant exons. Arrows indicate the relative orientation of the genes.

References:

  1. OMIM Entry 176640—Prion Protein; PRNP.
  2. Kretzschmar HA, Stowring LE, Westaway D et al. Molecular cloning of a human prion protein cDNA. DNA 1986; 5(4): 315-324. (PMID: 3755672)
  3. Puckett C, Concannon P, Casey C et al. Genomic Structure of the Human Prion Protein Gene. The American Journal of Human Genetics 1991; 49(2): 320-329. (PMID:1678248)
  4. Mahal SP, Asante EA, Antonious M et al. Isolation and functional characterisation of the promoter region of the human prion protein gene. Gene 2001; 268(1-2); 105-114. (PMID:11368906)
  5. Ciric D and Rezaei H. Biochemical insights into the prion protein family. Frontiers in Cell and Developmental Biology 2015; 3: 5. (PMID: 25717473)
  6. Harrison PM, Khachane A and Kumar M. Genomic assessment of the evolution of the prion protein gene family in vertebrates. Genomics 2010; 95(5): 268-277. (PMID: 20206252)
  7. Allais-Bonnet A and Pailhoux E. Role of the prion protein family in the gonads. Frontiers in Cell and Developmental Biology 2014; 2: 1-9. (PMID: 25364761)
  8. Mead S, Lloyd S and Collinge J. Genetic Factors in Mammalian Prion Diseases. Annual Review of Genetics 2019; 53: 117-147. (PMID: 31537104)
  9. Ehsani S, Tao R, Pcanschi CL et al. Evidence for Retrogene Origins of the Prion Gene Family. PLoS One 2011; 6(10): e26800. (PMID: 22046361)