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Prion Protein Mutation Database

Allele count in gnomAD: 0

Cases in literature: 1

Penetrance: Not yet established – more data needed

Clinical presentation:

62-year-old woman presented with difficulty in upper limb coordination and gait unsteadiness with falls. She is of Indonesian descent but has resided in Australia for sixteen years. Her past medical history includes diet-controlled type 2 diabetes mellitus, hypercholesterolaemia and hypertension. There was no known family history of dementia or other neurological disorder. The patient continued to deteriorate, with the development of disorientation, dysarthria, dysphagia and language difficulties; she died four months from symptom onset. Her clinical phenotype was characterised by a sub-acute supranuclear palsy-like syndrome1.

A supranuclear palsy-like presentation has also been associated with the following PRNP mutants: Phe198Ser2-3, Glu200Lys4, Arg208His5.

Neurological examination:

Examination shortly following presentation was remarkable for a severe abnormality of conjugate eye movements, with no vertical saccades to command and slow, stepwise horizontal saccades. Pursuit eye movements to target were broken and incomplete. Oculocephalic reflex eye movements were normal, consistent with a predominantly supranuclear deficit of ocular movements. Cranial nerve examination was otherwise normal. Her tone was normal in the limbs but increased in the neck and trunk. There was marked postural instability, with ambulation only possible with the assistance of two. Later, truncal and nuchal rigidity became more marked, saccadic and pursuit eye movements were lost and oculocephalic reflexes were suppressed1.

Clinical investigations:

CSF showed normal 14-3-3 proteins, but a mild elevation of total protein. EEG analysis showed non-specific excess of slower frequencies but no periodicity. Serial MR brain imaging, including DWI and FLAIR sequences, demonstrated only non-specific periventricular white matter changes thought to be ischaemic1.

Genetic analysis:

c.398C>T transition leading the GCC-to-GTC base change and an Ala133Val missense mutation. The single patient in whom this mutation has been identified to date, was homozygous for methionine at codon 129 and also carried the Glu219Lys polymorphism. Of note, the Ala133Val mutation was allelic with Lys219 1.

Neuropathological studies:

Microscopic examination demonstrated widespread, multi-focal spongiform encephalopathy. PrP-positive amyloid plaques were confined to the cerebellar molecular layer; most of the deposits formed cluster or multicentric plaques. No tau pathology was noted1.

Western blotting of brain homogenate for proteinase K resistant PrPSc species was not undertaken1.

Structure-based protein function annotation:

The C-terminal globular domain is formed of three α-helices (α1: aa 144-154, α2: aa 173-194, α3: 200-228), a short anti-parallel β-sheet (β1: aa 128-131 and β2: 161-164) and a single disulphide bond (Cys179-Cys214) connecting helices α2 and α3 6.

Ala133Val lies in the disordered β1-to-α1 linker region and is a perfectly conserved residue amongst mammalian species7-8 (see mammalian sequence alignment in Architecture of PrP). Alanine is, generally, a rather uninteresting residue. It is small, with a very short sidechain and therefore, is not particularly hydrophobic and is non-polar9. Substitution for valine, a Cβ-branched hydrophobic residue, would introduce a greater degree of bulkiness (∆ +46.9 Å3)10 near the PrPC backbone and restrict the conformations the main chain can adopt at this position. Although valine prefers to reside within β-strands9, molecular dynamic simulation studies indicate that mutant Ala133Val disrupts the short anti-parallel β-sheet by separation of strands β1 and β2 and this may represent the initial PrPC misfolding event11.

In silico Pathogenicity predictions:

Pon-P2 (independent)12:

  • Probability of pathogenicity: 0.637
  • Standard error: 0.057
  • Prediction: Unknown

Revel (ensemble)13:

  • Score: 0.717
  • Prediction: Non-pathogenic

A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.


  1. Rowe DB, Lewis V, Needham M et al. Novel prion protein gene mutation presenting with subacute PSP-like syndrome. Neurology 2007; 68(11): 868-870. (PMID: 17353478)
  2. Ufkes NA, Woodard C, Dale ML. A case of Gerstmann-Straussler-Scheinker (GSS) disease with supranuclear gaze palsy. Journal of Clinical Movement Disorders 2019; 6: 7. (PMID: 31890235)
  3. Yee RD, Farlow MR, Suzuki DA et al. Abnormal eye movements in Gerstmann-Straussler-Scheinker disease. Archives of Opthalmology 1992; 110(1): 68-74. (PMID: 1731725)
  4. Bertoni JM, Brown P, Goldfarb LG et al. Familial Creutzfeldt-Jakob disease (codon 200 mutation) with supranuclear palsy. Journal of the American Medical Association 1992; 268(17): 2413-2415. (PMID: 1404799)
  5. Matej R, Kovacs GG, Johanidesova S et al. Genetic Creutzfeldt disease with R208H mutation presenting as progressive supranuclear gaze palsy. Movement Disorders 2012; 27(4): 476-479. (PMID: 22488860)
  6. Zahn R, Liu A, Luhrs T et al. NMR solution structure of the human prion protein. Proceedings of the National Academy of Sciences USA 2000; 97(1): 145-150. (PMID: 10618385)
  7. Wopfner F, Weidenhöfer G, Schneider R et al. Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. Journal of Molecular Biology 1999; 289(5): 1163-1178. (PMID: 10373359)
  8. van Rheede T, Smolenaars MMW, Madsen O, de Jong WW. Molecular Evolution of the Mammalian Prion Protein. Molecular Biology and Evolution 2003; 20(1): 111-121. (PMID: 12519913)
  9. Betts MJ and Russell RB. Amino acid properties and consequences of substitutions. In Bioinformatics for Geneticists. Barnes MR, Gray IC eds. Wiley 2003.
  10. Pontius J, Richelle J, Wodak SJ. Deviations from standard atomic volumes as a quality measure for protein crystal structures. Journal of Molecular Biology 1996; 264(1): 121-136. (PMID: 8950272)
  11. Chen W, van der Kamp MW, Daggett V. Diverse effects on the native -sheet of the human prion protein due to disease-associated mutations. Biochemistry 2010; 49(45): 9874-9881. (PMID: 20949975)
  12. Niroula A, Urolagin S, Vihinen M. PON-P2: Prediction Method for Fast and Reliable Identification of Harmful Variants. PLoS One 2015; 10(2): e0117380. (PMID: 25647319)
  13. Ioannidis NM, Rothstein JH, Pejaver V et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. American Journal of Human Genetics 2016; 99(4): 877-885. (PMID: 27666373)