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

Deletions

Inserts

Silent nucleotide polymorphisms

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

Missense

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

Inserts

C: PRNP mutations associated with Creutzfeldt-Jakob Disease

Missense

** 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)

*** 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

E: PrP Cerebral Amyloid Angiopathy

Nonsense

F: PRNP mutations associated with less specific phenotypes

Missense

Inserts

Tentative Mutations awaiting Verification

* Patients harboring the mutation not pathologically examined.

References

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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.

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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.

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

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

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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.

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