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Prion Protein Mutation Database

Gly131Val/Arg


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Allele count in gnomAD: Gly131Val, 1; Gly131Arg 0

Cases in literature: Gly131Val, 5; Gly131Arg, 1

Penetrance: Not yet established – more data needed

Clinical presentation:

Gly131Val-Met129

This mutant, allelic with methionine at codon 129, has been found in five patients from three families: one Australian case1 without any family history, one Dutch patient of Indo-Asian descent2 and three cases from a Turkish kindred3. The clinical phenotype is dominated by personality change and a gradually deteriorating dementia that precedes the development of ataxia. This led to the misdiagnoses of frontotemporal dementia2 and familial Alzheimer’s disease3. Histopathologically, this mutant is associated with a GSS phenotype.

The mean age of onset (n = 4) is 37.5 years (range: 35 to 42 years, SD 3.1) and mean clinical duration-to-death (n = 3) is 130.7 months (range: 96 to 188 months, SD 50.0). One patient was alive 8 years into the disease process, and for one patient age of onset and clinical duration was not given (see Table of Cases below)

Gly131Arg-Val129

The Gly131Arg mutant has only been reported in one patient4 worldwide and is allelic with valine at codon 129. The mutant was found in an African American woman presenting aged 42 years with a rapidly deteriorating dementia causing death within 16 months of symptom onset. Histopathologic classification was not possible, however, the rapid clinical course and pronounced restricted diffusion on MR imaging supports an associated phenotype of CJD4. Therefore, we await neuropathologic evidence to determine whether the Gly131Arg-Val129 mutant induces a PrPSc strain causing CJD, rather than GSS.

Table of Cases:

MutationCase reportCountry of originNumber of DNA-confirmed Gly131Val patientsDetails of kindred and family members studiedGenderAge at onsetDuration of illness (months)Genotype at polymorphic sitesPresentation and other clinical details
Gly131ValPanegyres PK 2001 [1]Australia1The index patient’s family, including his two siblings who were in their 50s at time of reporting, and a teenage son had no history of neurologic disorder. Index patient’s two siblings were examined by the authors and were free of neurological signs – they declined genetic testing. Mutation thought to have arisen de novo.M42108Met/Met129Presented with personality change. Nine-year illness characterised by dementia and eventually ataxia. Neuropathologic studies were performed which revealed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration.
Gly131ValJansen C 2011 [2]Indo-Asia1Index case is Dutch but of Indo-Asian descent. His father had died of a similar dementia at the age of 44; he had personality changes, parkinsonism and dysarthric speech. The neuropathological examination of father mentioned severe frontal and cerebellar atrophy with plaque-like structures in the cerebellum – but neither slides nor tissue blocks could be retrieved by the authors.M36188Met/Val129 (Met in cis)Presented with personality change. His clinical phenotype was characterised by slowly progressive cognitive decline, later followed by ataxia and Parkinsonism. Neuropathological findings consisted of numerous PrPSc amyloid plaques in the cerebellum.
Gly131ValYetim E 2021 [3]Turkey3Turkish family. The proband (III-5) has a positive family history. A similar phenotype, dominated by progressive cognitive decline, reduced speech content, personality change and aggression was reported in index case’s father (II-5), one paternal uncle (II-9) and one paternal aunt (II-7), that started in the 4th or 5th decades and leading to death within ten years. The index patient (III-5), his affected and deceased father (II-5) and paternal uncle (II-9) are confirmed to harbour the Gly131Val mutant3 M35 (III-5)
37 (II-5)
Index case (III-5) alive at 96 months from onset
Father (II-5) died 96 months from onset
Met/Met129 (Index, III-5))
Met/Val129 (father II-5 and paternal uncle II-9, in cis residue not reported)
ApoE: e3/e3 in all three cases
Clinical phenotype in index patient is that of personality changes, behavioural disturbances and slowly progressive cognitive decline. A similar phenotype is reported in his father and paternal uncle. His father’s clinical onset was aged 37 years and he died 8 years later, aged 45. Clinical onset in the index patient was aged 35 years and he is alive 8 years from onset at time of report. No clinical details for the paternal uncle given. No neuropathology.
Gly131Arg*Alshaikh J 2020 [4]US1African American woman (II.C) with a significant family history of a mother (I.B) and sister (II.B) with a 4-5 year course of dementia and progressive gait dysfunction beginning in their 30s and 40s. The proband (II.C) has a daughter who is less than 30 years of age – she declined genetic testing.F4216Met/Val129 (Val in cis)
A single octapeptide repeat deletion, a known non-pathogenic polymorphism, was also present on the normal allele.
Rapidly progressive dementia and ataxia. The proband’s mother and sister had a similar phenotype but this developed at a slower pace, both died within 4-5 years.
Family declined post-mortem of proband.

F, female; M, male. *First reported in poster form: Alshaikh J, Qin K, Zhao L, Mastrianni J. A Novel PRNP-G131R Mutation Associated with Familial Prion Disease (P2.1-023). Neurology 2019; 92(15 Supplement).

Neurological examination:

 Neuropsychiatric disturbanceDementiaPyramidal signsExtrapyramidal signsCerebellar signsMyoclonus
Panegyres PK 2001 [1]

Gly131Val
Personality change. Aloofness, anxiety and aggression.Early impairment of short-term memory. Perseverance and emotional immaturity. Apraxia, tremor of the limbs and gegenhalten. Visuospatial skills were impaired and he was dyscalculic. MMSE 22/30, IQ 78.Brisk deep-tendon reflexesNoneAtaxia developed lateNone
Jansen C 2011 [2]

Gly131Val
Personality change. Delusions of grandeur, restlessness, aggression, apathy and flattening of affectEarly-onset cognitive impairment of gradual progression. Bradyphrenia and confabulations. Reduced spontaneous speech,
perseverations, stereotyped behaviour, apraxia and incontinence
NoneParkinsonism developed late. Masked facies, bradykinesia, rigidity of arms and legs, with cog-wheeling of armsDeveloped late in disease courseDeveloped late in disease course
Yetim E 2021 [3]

Gly131Val
Inappropriate laughter, disinhibited behaviours and hoarding. Apathy.Early onset cognitive impairment that progressed gradually. Disorientated in time. Executive functions, visuospatial ability and attention were impaired.NoneNoneNoneNone
Alshaikh J 2020 [4]

Gly131Arg
Inappropriate laughterRapidly progressing dementia. Disorientated in time and place. Non-fluent speech with minimal content. Bradyphrenia.Brisk upper limb reflexes and sustained ankle clonus. Plantars were flexor.NoneGait and truncal ataxiaNone

Clinical investigations:

  Gly131Val   Gly131Arg
  Panegyres PK 2001 [1] Jansen C 2011 [2] Yetim E 2021 [3]   Alshaikh J 2020 [4]
CSF analysis Normal, except for a slightly elevated protein concentration of 0.046 g/dL (normal range: 0.015-0.045 g/dL Not undertaken Not undertaken   Negative for infectious and inflammatory process. T-Tau was significantly elevated at 3026 pg/mL (values > 1150 pg/mL support prion disease). CSF analysis for 14-3-3 and RT-QuIC inconclusive due to contamination
EEG Normal (no periodic sharp waves) Diffuse hypofunctional changes but no periodic sharp waves Not undertaken   Slow (6-7 Hz) without periodic sharp wave complexes
Neuroimaging CT and MR brain imaging showed cerebral and cerebellar atrophy CT head showed mild atrophy of the cerebral cortex and cerebellum MR brain imaging revealed mild cerebral and cerebellar atrophy. No restricted diffusion seen on serial imaging. FDG-PET showed hypometabolism in bilateral temporal and parietal lobes, more pronounced in the right parietal lobe.   MR DWI brain showed restricted diffusion within the bilateral basal ganglia and in a ‘cortical ribboning’ pattern throughout multiple cortical regions, consistent with CJD.

Genetic analysis:

Gly131Val: c.392G>T leading to GGA-to-GTA. Where reported this mutation occurs in cis with methionine at codon 129.

Gly131Arg: c.391G>A leading to GGA-to-AGA. This mutant is found to occur in cis with valine in the single patient in which it has been found thus far.

Neuropathological studies:

Gly131Val

The brains of the two patients that underwent neuropathologic analysis1-2 showed numerous PrP amyloid plaques in the molecular layer of the cerebellum; the frontal, parietal, and temporal cortices; the striatum; and the thalamus. These were accompanied by hyperphosphorylated tau deposition but without spongiform deposition. However, the neuropathologic findings were more severe for the patient reported by Jansen and colleagues2; PrP amyloid plaques were present in more areas of the brain, including the occipital cortex, midbrain and amygdala. Tau deposits were also more numerous, and unlike in the brain reported by Panegyres and colleagues1, they were not just restricted to the Ammon horn and entorhinal cortex1 and were also co-localised with PrP amyloid plaques2. The more extensive PrP deposits in the patient of Jansen et al2 are likely due to the longer disease duration in this patient, 188 months (15 years and eight months), as compared to 108 months (nine years)1.

Immunoblotting of cerebellum homogenate reveals proteinase K-resistant PrPSc species of approximately 8, 18, 26 and 31 kDa by Panegyres et al1 and of approximately 8 kDa, 17 kDa and other higher-molecular weight bands by Jansen et al2.

Gly131Arg

No neuropathological analysis, as yet, unavailable.

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 α-helices 2 and 3 5; Glycine 131 forms the last residue of the first β-strand in PrPC and is position of perfect conservation among mammalian species6-7 (See Architecture of PrP).

Glycine is a small and unique residue, that has a hydrogen as its sidechain (rather than a carbon as in all other amino acids) giving it conformational flexibility. Therefore, substitution of this highly conserved glycine to valine, a Cβ-branched hydrophobic residue that would introduce a greater degree of bulkiness (∆ +70.9 Å3)8 near the PrPC protein backbone and restrict the conformations the main chain can adopt at this position; however, it is easy and even preferred for valine residues to reside within β-strands9. Indeed, molecular dynamic simulations performed on the monomeric Gly131Val mutant (modelled on wild-type human PrP pdb structure: 1QLX5) suggest that this mutant induces the formation of two additional hydrogen bonds between the main chains of strands β1 and β2 10. In wild-type human PrP there are four main chain hydrogen bonds in the PrP β-sheet: Met129 N-O Tyr163, Met129 O-N Tyr163, Gly131 N-O Val161 and Met134 N-O Asn159 5. Simulation (for 49 ns) of mutant Gly131Val induces formation of two new stable hydrogen bonds, V131 O-N Val161 and Ala133 N-O Asn159, and breaks hydrogen bond Met134 N-O Asn159, which in turn results in elongation of the native PrPC β-sheet10. In a much shorter simulation of 4 ns, strand β1 was also seen to extend by on average two residues11. The bulkiness of valine at position 131 and its steric effects on neighbouring Ser132 residue was the initiating event in hydrogen-mutant Gly131Val bond reshuffling10, although the thermodynamic stability of mutant PrP is unaffected12.

Enhanced β-sheet stability in mutant Gly131Val may drive PrPC-to-PrPSc conversion; Gly131Val PrP (aa 23-231) was found to exhibit a significantly enhanced oligomerisation rate compared to wild-type and contrarily, decreased its fibrillisation tendency12. These authors also showed that the 2D 1H-15N HSQC spectra of wild-type and Gly131Val PrP do not overlay particularly well for peaks corresponding to Gly131 and the nine neighbouring residues within 5 Å distance12, indicating that there are local structural perturbations that may be related to the predicted β-sheet extension simulated in this mutant10-11.

Substitution of a large, positively charged, linear arginine at position 131 results in 128.6 Å3 increase in volume at this site with significant predicted atomic van der Waal radii overlap with surrounding residues. As such, mutant Gly131Arg would be expected to cause substantial local structural perturbations.

In silico Pathogenicity predictions:

Pon-P2 (independent)13:

  Gly131Val Gly131Arg
Probability of pathogenicity 0.886 0.946
Standard error 0.082 0.029
Prediction Pathogenic Pathogenic

Revel (ensemble)14:

  Gly131Val Gly131Arg
Score 0.861 0.847
Prediction Pathogenic Pathogenic

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

References:

  1. Panegyres PK, Toufexis K, Kakulas BA et al. A new PRNP mutation (G131V) associated with Gerstmann-Straussler-Scheinker disease. Archives of Neurology 2001; 58(11): 1899-1902. (PMID: 11709001)
  2. Jansen C, Parchi P, Capellari S et al. A second case of Gerstmann-Straussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient. Journal of Neuropathology and Experimental Neurology 2011; 70(8): 698-702. (PMID: 21760536)
  3. Yetim E, Gul T, Basak AN, Saka E. An unusual familial dementia associated with G131V PRNP mutation. European Journal of Neurology 2021; 28(2): 377-380. (PMID: 32986314)
  4. Alshaikh JT, Qin K, Zhao L, Mastrianni JA. A novel PRNP-G131R variant associated with familial prion disease. Neurology Genetics 2020; 6(4): e454. (PMID: 32637633)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  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. 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)
  11. Santini S, Claude J-B, Audic S, Derreumaux P. Impact of the tail and mutations G131V and M129V on prion protein flexibility. Proteins 2003; 51(2): 258-265. (PMID: 12660994)
  12. Zhang M, Zhang H, Yao H et al. Biophysical characterisation of oligomerisation and fibrillisation of the G131V pathogenic mutant of human prion protein. Acta Biochimica et Biophysicia Sinica 2019; 51(12): 1223-1232. (PMID: 31735962)
  13. 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)
  14. 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)