Molecular Genetics of Creutzfeldt–Jakob Disease and Gerstmann– Sträussler– Scheinker Disease

Abstract

Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes of human prion diseases or transmissible spongiform encephalopathies (TSEs). TSEs arise either spontaneously (sporadic disease forms such as sporadic CJD/sCJD or sporadic fatal insomnia/sFI), by genetic aberration (genetic CJD/gCJD, GSS, fatal familial insomnia/FFI) or acquired by contact with infectious prions from bovine spongiform encephalopathy (BSE), causing variant CJD (vCJD), or – more or less historically – as iatrogenic CJD (iCJD) from invasive medical procedures such as dural or corneal transplantations, cadaveric pituitary hormone preparations or surgical instruments, or from blood and blood products with vCJD prions. Genetic forms constitute about 10–15% of human prion diseases and result from more than 30 mutations, insertions or rarely deletions in the prion protein (PrP) gene, PRNP. A polymorphism at PRNP codon 129 is an important susceptibility factor and relevant for phenotypic heterogeneity. Other genes have not convincingly been shown to be involved.

Key Concepts

  • Prion diseases are invariably lethal and transmissible neurological disorders that affect humans and animals.
  • In humans, they occur sporadically and can also be acquired or inherited.
  • The infectious agent is considered to be solely an abnormal conformer of the host‐encoded prion protein (PrP).
  • Genetic disease forms constitute about 10–15%, result from aberrations in the PrP gene, PRNP, and are inherited as autosomal dominant trait with variable penetrance.
  • There is a broad clinical and neuropathological phenotypic spectrum, which is modulated by molecular factors including PRNP polymorphisms and PrP strains.
  • Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker disease (GSS) are distinct clinicopathological phenotypes.
  • CJD occurs mostly sporadically (sCJD), more rarely by genetic aberration (gCJD), whereas GSS is always of genetic origin.
  • There is no effective treatment yet.

Keywords: Prion diseases; Creutzfeldt–Jakob disease (CJD); Gerstmann–Sträussler–Scheinker disease (GSS); prion strains; molecular typing; PRNP; genetic disease

Figure 1. PRNP, PrP structure and molecular typing in sCJD. Structural features of the human prion protein (PrP) gene (PRNP) and the human PrP. Shown are the signal regions (dark grey), the octapetide repeat region (red) and the regions of predicted alpha‐helical or beta‐sheet secondary structures (orange and dark orange, respectively). Glycosylation sites are shown in brown (aa181 and 197) and the disulfur bound in black lines (S–S, aa179 and 214). Black arrowheads indicate the main residues cleaved by proteinase K. The C‐terminal region from this point to aa231 is considered to be the protease‐resistant core. The possible fragments resulting from proteinase K digestion are shown in the left part of the immunoblot diagram. Each fragment is supposed to have a molecular weight depending on the glycosylation pattern (di‐, mono‐ or unglycosylated; the monoglycosylated fragment can have the sugar bound to either ASp 197 or Asp 181). A diagram of the predicted immunoblot bands of each fragment and their corresponding approximate molecular weight is represented on the right. Subtypes of sporadic CJD are classified according to the amino acid present at position 129 (in purple). Depending on whether methionine (M) or valine (V) is present, and on the homozygosis or heterozygosis status, the immunoblot pattern of PrPres and immunohistochemical findings may differ. In the bottom part of the diagram, representative immunohistochemical patterns of PrPsc immunoreactivity that define each subtype of sCJD are shown. Abbreviations: PK, proteinase K; kDa, kiloDaltons; sCJD, sporadic CJD and GPI, glycosyl‐phosphatidyl‐inositol.
Figure 2. PRNP mutations and polymorphisms. Schematic representation of the secondary structure of PRNP, showing the signal regions (dark grey), the octapetide repeat region (red) and the regions of predicted alpha‐helical or beta‐sheet secondary structures (orange and dark orange, respectively). The upper part of the figure shows the most common mutations associated with a GSS (green), CJD (blue) or FFI (brown) phenotype, and the lower part the most common polymorphisms (purple). One to six octapeptide repeat insertions (OPRIs) have usually a CJD‐like phenotype, whereas 6–12 OPRIs a GSS‐like one (six OPRIs may feature both). Abbreviation: GPI, glycosyl‐phosphatidyl‐inositol.
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Further Reading

Budka H (2007) Portrait of Creutzfeldt‐Jakob. In: Hörnlimann B, Riesner D and Kretzschmar H (eds) Prions in Humans and Animals, pp. 195–203. Berlin – New York: DeGruyter.

Dickson DW and Weller RO (2009) Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, 2nd edn. Oxford‐Chichester‐Hoboken, NJ: Wiley‐Blackwell.

European Creutzfeldt Jakob Disease Surveillance Network (2015) http://www.eurocjd.ed.ac.uk/

Head MW, Ironside JW, Ghetti B, et al. (2015) Prion diseases. In: Love S, Budka H, Ironside JW and Perry A (eds) Greenfield's Neuropathology, 9th edn, vol. 2, chapter 18, pp. 1016–1086. Boca Raton, FL: CRC Press.

Information on Bovine spongiform encephalopathy (2015) http://www.who.int/zoonoses/diseases/bse/en/

Questions and answers regarding Creutzfeldt‐Jakob disease infection‐control practices (2003) http://www.cdc.gov/ncidod/dvrd/cjd/qa_cjd_infection_control.htm

The Human Gene Mutation Database (2015). http://www.hgmd.cf.ac.uk/ac/index.php

WHO infection control guidelines for transmissible spongiform encephalopathies (1999) http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000_3/en/

WHO guidelines on tissue infectivity distribution in TSE (2006) http://www.who.int/bloodproducts/TSEPUBLISHEDREPORT.pdf?ua=1; http://www.who.int/bloodproducts/tse/en/

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Gelpi, Ellen, Colom‐Cadena, Marti, and Budka, Herbert(Jun 2015) Molecular Genetics of Creutzfeldt–Jakob Disease and Gerstmann– Sträussler– Scheinker Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024442]