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Mutations and normal polymorphisms in the prion protein gene (PRNP) open reading frame

The following tables are grouped according to disease and attempt to give a comprehensive summary of all known mutations and normal variations in the prion protein gene (PRNP) open reading frame (i.e. amino acid coding portion of the gene) on chromosome 20(p12-pter). The open reading frame lies entirely within exon 3 of PRNP. It is frequently updated as new mutations are reported. The following tables do not list nucleotide variations located outside the open reading frame of PRNP, and at present there are no reported disease–associated mutations lying in either exons 1 or 2, nor within any of the introns.

There are two main forms of mutations associated with prion disease: point changes (i.e. single nucleotide substitutions or transversions) which cause an amino acid change (missense mutation) or less commonly cause the coding to prematurely terminate (stop or nonsense mutation). Single nucleotide changes that do not cause alteration in the amino acid are known as "silent", and are generally not regarded as significant. The second type of mutation associated with prion diseases consists of inserts. In the normal situation, the nucleotide sequence from codons 51 to 91 codes for a nonapeptide followed in tandem by four identical octapeptide repeats which are also almost identical to the nonapeptide (except for the omission of a glycine). The insert mutations consist of octapeptide repeats varying from 1 to 9 in total length, although an insert of 3 octapeptides has not yet been reported in association with prion disease. All inserts lie within the repeat section of the open reading frame from codon 51 to 91, and while having minor variations in the exact nucleotide sequence, they all code for the same amino acids found in the wild type protein octapeptide repeat segment. A single octapeptide repeat is occasionally found deleted in PRNP and believed to represent a normal polymorphism.

Mutations found in symptomatic patients but not yet verified pathologically are regarded as tentative and grouped separately.

 

A: Normal Polymorphisms of PRNP

Codon

  

References

129

either methionine or valine (caucasian population: met homozygous 37%; met/val heterozygous 51%; val homozygous 12%).

Palmer 1991

219

approximately 88% of Japanese population have glutamate (GAG), while 12% have lysine (AAG).

Furukawa 1995

 

Deletions

Single octapeptide repeat (24 bp) deletions; 3 types described, varying in specific nucleotide position, but all lying within the 5 octapeptide repeat region betweencodons 51 to 91; present ~ 1% of population

Palmer 1993;
Windl et al. 1999

 

Inserts

4 octapeptide repeat (96 bp) insert; found in a 63 year old male dying from micronodular cirrhosis and no personal or family history of neurological disease.

Goldfarb 1991

 

Silent nucleotide polymorphisms

Codon

Codon change

% Population frequency

References

P68P

CCT => CCC

<1

Windl et al. 1999

A117A

GCA => GCG

5-10

Wu et al. 1987

G124G

GGC => GGG

0.5

Prusiner 1997

V161V

GTG => GTA

  

Prusiner 1997

H177H

CAC => CAT

  

Ripoll 1993

Q212Q

CAG => CAA

<1

Windl et al. 1999

R228R

AGA => AGG

<1

Windl et al. 1999

S230S

TCG => TCA

<1

Windl et al. 1999

 

B: PRNP mutations associated with Gerstmann-Sträussler-Scheinker Syndrome

Missense

Codon

Amino acid change

cis-codon 129

Reference morphism

102

proline to leucine

methionine*

Hsiao 1989

105

proline to leucine

valine

Kitamoto 1993a

117

alanine to valine

valine

Doh-ura 1989

198

phenylalanine to serine

valine

Hsiao 1992

202

aspartate to asparagine

valine

Piccardo 1998

212

glutamine to proline

not stated

Piccardo 1998

217

glutamine to arginine

valine

Hsiao 1992

* This mutation has also been reported incis with valine at codon 129 (Young 1997).

 

Inserts

8 octapeptide repeat (192 bp) insert starting at codon 84

Goldfarb 1991a (and Goldfarb 1992 for fuller description)

8 octapeptide repeat (192 bp) insert starting at codon 76; different nucleotide sequence to the other octapeptide repeats descibed in the other two GSS families; in cis with valine at codon 129; clinical phenotype has parkinsonism and very little cerebellar ataxia.

van Gool 1995

8 octapeptide repeat (192 bp) insert); specific site not stated but located within codon 51 to 91 region; different family to Goldfarb 1992 report; cis to met at codon 129.

El Hachimi 1998

8 octapeptide repeat (192 bp) insert (French M-E kindred); probably starts at codon 84; cis to met at codon 129. Different 192 bp insert (at nucleotide level) to that described in the families of Goldfarb and van Gool.

Laplanche 1999

 

C: PRNP mutations associated with Creutzfeldt-Jakob Disease

Missense

Codon

Amino acid change

cis-codon 129 morphism

Reference

178

aspartate to asparagine

valine

Goldfarb 1991b

180

valine to isoleucine

not stated

Kitamoto 1993a

188

threonine to alanine

methionine

Collins 2000

196

glutamate to lysine

methionine

Peoc’h 2000

200**

glutamate to lysine

val or met

Goldgaber 1989

203

valine to isoleucine

methionine

Peoc’h 2000

208

arginine to histidine

methionine

Mastrianni 1996

210

valine to isoleucine

methionine

Pocchiari 1993

211

glutamate to glutamine

methionine

Peoc’h 2000

232

methionine to arginine

not stated

Kitamoto 1993a

** The codon 200 mutation may be associated with insomnia as the main clinical characteristic (Chapman 1996).

 

Inserts (all occur in the coding region from codon 51 to 91)

1 octapeptide

repeat (24 bp) insert

Laplanche 1995

2 octapeptide

repeat (48 bp) insert

Goldfarb 1993

4 octapeptide

repeat (96 bp) insert

Laplanche 1995 (Campbell 1996)

5 octapeptide

repeats (120 bp) insert***

Goldfarb 1991a

6 octapeptide

repeat (144 bp) insert****

Owen 1989

7 octapeptide

repeat (168 bp) insert

Goldfarb 1991a

*** Three different 120bp octapeptide repeat inserts have been reported, with some members manifesting typical CJD but significant intra-familial pheotypic variation a feature. Windl et al. 1999; Cochran et al. Neurology 1996; 47: 727-733.

**** However, the 144 bp insert is associated with a diverse range of symptomatic phenotypes within families, ranging from typical CJD through atypical dementia (mimicking Alzheimer’s disease) to typical GSS with the neuropathology ranging from typical spongiform encephalopathy to essentially normal: Collinge et al. 1992.

 

D: PRNP mutations associated with Fatal Familial Insomnia

Missense

Codon

Amino acid change

cis-codon 129 morphism

Reference

178

aspartate to asparagine

methionine

Medori 1992

 

E: PrP Cerebral Amyloid Angiopathy

Nonsense

Codon

Amino acid change

cis-codon 129

Reference

145

tyrosine to stop

methionine

Ghetti 1996 (Kitamoto 1993b)

 

F: PRNP mutations associated with less specific phenotypes

Missense

Codon

Amino acid change

Phenotype

Reference

171

Asparagine to serine(cis valine at codon 129)

Familial neuro- psychiatric illness (psychotic depression, violent behaviour, some also have dementia; others only psychiatric problems).

Samaia 1997

183

Threonine to alanine

Presenile dementia in Brazilian family; fronto-temporal emphasis duration 2-9 years; parkinsonism commonly seen;

Nitrini 1997

183

Threonine to alanine

Familial Alzheimer’s disease; 4 year duration (with dementia)

Nitsch 1998

 

Inserts

6 octapeptide

repeat (144 bp) insert

Variable including CJD, GSS, "Alzheimer’s", atypical dementia, "Huntington’s", etc.

Collinge 1992

 9 octapeptide

repeat (216 bp) insert

sporadic dementia; 2.5 year duration; no spongiform change but PrP+ve plaques.

Owen 1991

 

Tentative Mutations awaiting Verification

Codon

Amino acid change

Phenotype

Reference

188*

threonine to arginine

not cited

Windl et al. 1999

238*

proline to serine

not cited

Windl et al. 1999

187*

histidine to arginine

GSS-like

Cervenáková 1999

188*

threonine to lysine

CJD-like

Finckh et al. 2000

160*

glutamine to stop

GSS-like

Finckh et al. 2000

* Patients harboring the mutation not pathologically examined.


References

  1. Palmer M, et al. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352: 340-342.

  2. Furukawa H, et al. New variant prion protein in a Japanese family with Gerstmann-Straussler syndrome. Molecular Brain Research 1995; 30: 385-388.

  3. Palmer M, et al. Deletions in the prion protein gene are not associated with CJD. Human Molecular Genetics 1993; 2: 541-544.

  4. Goldfarb L, et al. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci 1991a; 88: 10926-10930.

  5. Hsiao K, et al. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 1989; 338: 342-345.

  6. Kitamoto T, et al. Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstamnn-Straussler syndrome. Biochem Biophys Res Comm 1993a; 191: 709-714.

  7. Doh-ura K, et al. Pro =>Leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Straussler syndrome. Biochem Biophys Res Comm 1989; 163: 974-979.

  8. Kitamoto T, et al. An amber mutation of prion protein in Gerstmann-Straussler syndrome with mutant PrP plaques. Biochem Biophys Res Comm 1993b; 192: 525-531.

  9. Hsiao K, et al. Mutant prion proteins in Gerstamnn-Straussler-Scheinker disease with neurofibrillary tangles. Nature Genetics 1992; 1: 68-71.

  10. Piccardo P, et al. Physicochemical properties of prion protein (PrP) Gerstmann-Straussler-Scheinker disease (GSS) Q212P. Soc Neurosci Abstr. 1998; 24 part 1: 1476.

  11. Goldfarb L, et al. An insert mutation in the chromosome 20 amyloid precursor gene in a Gerstmann-Straussler-Scheinker family. J Neurol Sci 1992; 111: 189-194.

  12. van Gool W, et al. Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein gene. Brain 1995; 118: 1565-1571.

  13. El Hachimi K, et al. An insert mutation in the PrP gene in a French Gerstmann-Straussler-Scheinker family with psychiatric features. Soc Neurosci Abstr. 1998; 24 part 1: 1476.

  14. Young K, et al. Gerstmann-Straussler-Scheinker disease with the PRNP P102L mutation and valine at codon 129. Mol Brain Research 1997; 44: 147-150.

  15. Goldfarb L, et al. New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfedt-Jakob kindred. Lancet 1991b; 337: 425.

  16. Mastrianni J, et al. Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. Neurology 1996; 47: 1305-1312.

  17. Goldgaber D, et al. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker’s syndrome. Experimental Neurology 1989; 106: 204-206.

  18. Pocchiari M, et al. A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease. Ann Neurol 1993; 34: 802-807.

  19. Goldfarb L, et al. A new (two-repeat) octapeptide coding insert mutation in Creutzfeldt-Jakob disease. Neurology 1993; 43: 2392-2394.

  20. Laplanche JL et al. Two novel insertions in the prion protein gene in patients with late-onset dementia. Hum Mol Genet 1995;4: 1109-1111.

  21. Campbell T, et al. A prion disease with a novel 96-base pair insertional mutation in the prion protein gene. Neurology 1996; 46: 761-766.

  22. Owen F, et al. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet 1989; I: 51-52.

  23. Collinge J, et al. Inherited prion disease with 144 base pair gene insertion; 2. clinical and pathological features. Brain 1992; 115: 687-710.

  24. Medori R, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. NEJM 1992; 326: 444-449.

  25. Chapman J, et al. Fatal insomnia in a case of familial Creutzfeldt-Jakob disease with the codon 200lys mutation. Neurology 1996; 46: 758-761.

  26. Samaia H, et al. A prion-linked psychiatric disorder. Nature 1997; 390: 242.

  27. Nitrini R, et al. Familial spongiform encephalopathy associated with a novel prion protein gene mutation. Ann Neurol 1997; 42: 138-146.

  28. Nitsch R, et al. A clinical syndrome similar to familial Alzheimer’s disease caused by a T183A mutation of the prion protein. Soc Neurosci Abstr. 1998; 24 part 1: 1476.

  29. Owen F, et al. Insertions in the prion protein gene in atypical dementias. Experimental Neurology 1991; 112: 240-242.

  30. Ghetti B, Piccardo P, Spillantini MG et al. Vascular variant of prion protein cerebral amyloidosis with t -positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc Natl Acad Sci 1996; 93: 744-748.

  31. Collins S, Boyd A, Fletcher A, et al. Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease. Arch Neurol 2000; 57: 10

  32. Windl O, Giese A, Schulz-Schaeffer W et al. Molecular genetics of human prion diseases in Germany. Hum Genet 1999; 105: 244-252.

  33. Wu Y, Brown WT, Robakis NK, et al. A PvuII RFLP detected in the human prion protein (PrP) gene. Nucleic Acids Res 1987; 15: 3191.

  34. Cervenáková L, Buetefisch C, Lee H-S, et al. Novel PRNP sequence variant associated with familial encephalopathy. Neuropsychiatr Genet 1999; 88: 653-656.

  35. Finckh U, Müller-Thomsen T, Mann U, et al. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 2000; 66: 110-117.

  36. Laplanche J-L, El Hachimi KH, Durieux I, et al. Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene. Brain 1999; 122: 2375-2386.

  37. Prusiner SB. Prion diseases and the BSE crisis. Science 1997; 278: 245-250.

  38. Ripoll L, Laplanche J-L, Salzmann M, et al. A new point mutation in the prion protein gene at codon 210 in creutzfeldt-Jakob disease. Neurology 1993; 43: 1934-1938.

  39. Peoc’h K, Manivet P, Beaudry P, et al. Identification of three novel mutatons (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype. Human Mutation 2000 #323.

  40. Piccardo P, Dlouhy SR, Lievens PM, et al. Phenotypic variability of Gerstmann-Straussler-Schinker disease is associated with prion protein heterogeneity. J N Exp Neur 1998; 57: 979-988.