Allele count in gnomAD: 0
Cases in literature: 1
Penetrance: Not yet established – more data needed
This mutation has only been described in one UK family to date1; only the proband is genetically confirmed to harbour the Ser132Ile mutant, with homozygosity for methionine at codon 129. However, her brother died aged 46 years (clinical onset aged 39), following a seven-year history of a progressive ataxic disorder with dementia. Her mother died aged 58 years, maternal grandfather at 60 years and great grandfather at 66 years of age; none of these family members underwent genetic or neuropathological investigation. Clinical onset in the proband was at age 61 years with progressive cognitive decline, and she died 30 months from symptom onset.
The pathological features of this case suggest an associated GSS phenotype1.
The proband was found to have impairment of visuospatial tasks, mild frontal signs and impairment of short-term memory. MMSE score was 14/30. Cerebellar signs were not noted at any stage of disease1.
CSF and EEG examinations were not performed. CT head was normal1.
c.395G>T resulting in the AGT-to-ATT base change and the Ser132Ile missense mutation. The single patient in which this mutation has been found is homozygous for methionine at codon 1291.
There were numerous amyloid plaques in the neocortex, basal ganglia, thalamus and cerebellum; which were a mixture of large diffuse (up to 310 m in diameter) and more compact unicentric and multicentric amyloid plaques, which showed strong PrP immunoreactivity. There was minimal spongiform change in the cerebral and cerebellar cortices. There was moderate tau pathology associated with PrP plaques1.
Western blot analysis of proteinase K treated frontal lobe homogenate showed two small fragments of less than 10 kDa ( 9 kDa and 7 kDa)1.
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 2.
Serine 132 lies in the disordered β1-to-α1 linker region and is a perfectly conserved residue amongst mammalian species3-4. Serine is a small neutral residue; its substitution to the Cβ-branched isoleucine introduces a bulkier aliphatic, hydrophobic residue (∆+60.6 Å3)5, that although would not be predicted to clash with neighbouring residues has been shown by molecular dynamic simulation6 to induce the formation of an α-sheet. This is an atypical secondary structure formed by regular hydrogen bonding between adjacent strands in the ‘α-extended chain’ conformation. Rather than being formed by average repeating (Φ,Ψ) angles, as with the α-helix and β-strand, the α-extended chain conformation is defined by alternation of residues in the right-handed and left-handed conformations7. While each residue is locally defined as helical, the alternation leads to formation of an extended sheet. This structure contains glide plane symmetry such that Φi = Φi+1 and Ψi = Ψ i+17. It is hypothesised by the Daggett group7-8, that the α-sheet may represent the toxic conformer in amyloid diseases.
Interestingly, Chen and colleagues6 found that simulation of this mutant converted the native β-sheet into an α-sheet and further extended it to three strands with participation of N-terminal residues Val122, Gly123, Gly124 and Gly1266. In the α-sheet, the main chain amide groups are on one side and the carbonyl groups are on the other side, forming a polar sheet (as initially described by Pauling and Corey, as a polar pleated sheet9. This arrangement is suggested to give rise to attractive forces for self-association and thus, facilitate formation of amyloid protofibrils7-8.
In silico Pathogenicity predictions:
- Probability of pathogenicity: 0.807
- Standard error: 0.055
- Prediction: Pathogenic
- Score: 0.776
- Prediction: Pathogenic
A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.
- Hilton DA, Head MW, Singh VK et al. Familial prion disease with a novel serine to isoleucine mutation at codon 132 of prion protein gene (PRNP). Neuropathology and Applied Neurobiology 2009; 35(1): 111-115. (PMID: 19187063)
- 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)
- 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)
- 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)
- 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)
- 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)
- Daggett V. Alpha-sheet: The toxic conformer in amyloid diseases? Accounts of Chemical Research 2006; 39(9): 594-602. (PMID: 16981675)
- Armen RS, DeMarco ML, Alonso DOV, Daggett V. Pauling and Corey’s -pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease. Proceedings of the National Academy of Sciences USA 2004; 101(32): 11622-11627. (PMID: 15280548)
- Pauling L and Corey RB. The pleated sheet, a new layer configuration of polypeptide chains. Proceedings of the National Academy of Sciences USA 1951; 37: 251-256. (PMID: 14834147)
- 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)
- 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)