This data was extracted from Medline abstracts and full texts (when available) in an automated manner.
The table below describes different point mutations at a given position and provides links to other documents. The sentence(s) where the point mutations in PRIO_HUMAN at position 217 were found are listed after the table.
| Protein | PRIO_HUMAN (P04156) Gene: PRNP (other point mutations) | Swiss-Prot
Cross-reference table
Family page |
| Position | Q217 | |
| General numbering (PrionDB) | - |
| Domain | Not determined |
| Family alignments |
Mammalian prion proteins
Prion proteins (PRP, PRNP)
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| Other point mutations at the same position |
Position 217 in Mammalian prion proteins family
Position 217 in Prion proteins (PRP, PRNP) family
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| Reference #1 | Zanusso G, Petersen RB, Jin T, Jing Y, Kanoush R, Ferrari S, Gambetti P, Singh N
J Biol Chem 1999 Aug 13;274(33):23396-404. | Medline |
| Text source | HTML and PDF full texts |
| Point mutation | Q217R (True positive) | |
| Reference #2 | Zuegg J, Gready JE
Biochemistry 1999 Oct 19;38(42):13862-76. | Medline |
| Text source | HTML and PDF full texts |
| Point mutation | Q217R (True positive) | |
| Reference #3 | Capellari S, Parchi P, Russo CM, Sanford J, Sy MS, Gambetti P, Petersen RB
Am J Pathol 2000 Aug;157(2):613-22. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (True positive) | |
| Reference #4 | Jin T, Gu Y, Zanusso G, Sy M, Kumar A, Cohen M, Gambetti P, Singh N
J Biol Chem 2000 Dec 8;275(49):38699-704. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (True positive) | |
| Reference #5 | Tagliavini F, Lievens PM, Tranchant C, Warter JM, Mohr M, Giaccone G, Perini F, Rossi G, Salmona M, Piccardo P, Ghetti B, Beavis RC, Bugiani O, Frangione B, Prelli F
J Biol Chem 2001 Feb 23;276(8):6009-15. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (True positive) | |
| Reference #6 | Piccardo P, Liepnieks JJ, William A, Dlouhy SR, Farlow MR, Young K, Nochlin D, Bird TD, Nixon RR, Ball MJ, DeCarli C, Bugiani O, Tagliavini F, Benson MD, Ghetti B
Am J Pathol 2001 Jun;158(6):2201-7. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (True positive) | |
| Reference #7 | Ivanova L, Barmada S, Kummer T, Harris DA
J Biol Chem 2001 Nov 9;276(45):42409-21. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #8 | Yedidia Y, Horonchik L, Tzaban S, Yanai A, Taraboulos A
EMBO J 2001 Oct 1;20(19):5383-91. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #9 | Ma J, Lindquist S
Proc Natl Acad Sci U S A 2001 Dec 18;98(26):14955-60. | Medline |
| Text source | HTML and PDF full texts |
| Point mutation | Q217R (True positive) | |
| Reference #10 | Mastrangelo P, Serpell L, Dafforn T, Lesk A, Fraser P, Westaway D
FEBS Lett 2002 Dec 4;532(1-2):21-6. | Medline |
| Text source | HTML and PDF full texts |
| Point mutation | Q217R (True positive) | |
| Reference #11 | Roucou X, Guo Q, Zhang Y, Goodyer CG, LeBlanc AC
J Biol Chem 2003 Oct 17;278(42):40877-81. Epub 2003 Aug 12. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #12 | Apetri AC, Surewicz K, Surewicz WK
J Biol Chem 2004 Apr 23;279(17):18008-14. Epub 2004 Feb 2. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (True positive) | |
| Reference #13 | De Simone A, Dodson GG, Verma CS, Zagari A, Fraternali F
Proc Natl Acad Sci U S A 2005 May 24;102(21):7535-40. Epub 2005 May 13. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #14 | Singh N, Zanusso G, Chen SG, Fujioka H, Richardson S, Gambetti P, Petersen RB
J Biol Chem 1997 Nov 7;272(45):28461-70. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #15 | Parchi P, Chen SG, Brown P, Zou W, Capellari S, Budka H, Hainfellner J, Reyes PF, Golden GT, Hauw JJ, Gajdusek DC, Gambetti P
Proc Natl Acad Sci U S A 1998 Jul 7;95(14):8322-7. | Medline |
| Text source | HTML full text |
| Point mutation | Q217R (Not yet checked) | |
| Reference #16 | Riek R, Wider G, Billeter M, Hornemann S, Glockshuber R, Wuthrich K
Proc Natl Acad Sci U S A 1998 Sep 29;95(20):11667-72. | Medline |
| Text source | HTML and PDF full texts |
| Point mutation | Q217R (True positive) | |
Reference #1 (Zanusso G et al.): Q217R
- 1 , A versus B) raises the possibility that this form is not immunoprecipitated efficiently because of a change in its conformation , as previously observed with the PrP M Q217R (19 ) (see below)
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Reference #2 (Zuegg J et al.): Q217R
- The amino acid residues in black boxes are mutation sites known to be associated with inherited forms of PrP diseases in humans [CJD , D178N:129V (3) , V180I (3) , T183A (3) , E200K (3) , R208H (3) , V210I (3) , and M232R (3) ; GSS , P102L (3) , P105L (3) , A117V (3) , Y145Stop (3) , H187R (14) , F198S (3) , D202N (13) , Q212P (13) , and Q217R (3) ; FFI , D178N:129M (3) ; schizophrenia , N171S (12) ] , while in light gray boxes residues involved in some polymorphisms influencing these diseases are shown [M129V (3) , E219K (11) ]
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Reference #3 (Capellari S et al.): Q217R
- The underrepresentation of UPrP M in the cell model is a feature shared by the Q217R and the D178N mutations 23 and is common to the E200K and D178N familial variants of CJD and to Fatal Familial Insomnia
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Reference #4 (Jin T et al.): Q217R
- We have examined the role of molecular chaperones in the folding of normal and mutant PrP Q217R (PrP217) in transfected neuroblastoma cells
- We have now studied the folding and turnover of PrP32 to understand the mechanism by which abnormal PrP forms cause cellular toxicity in our cell culture model and in the human brain carrying the Gerstmann-Sträussler-Scheinker disease Q217R mutation
- The mutation at PRNP codon 217 resulting in the substitution of glutamine to arginine (Q217R) in the mutant PrP (PrP217) is associated with a GSS disease phenotype that presents in the seventh decade and is characterized by a slowly progressive dementia associated with cerebellar and extrapyramidal signs (10 )
- The histopathological hallmark of the Q217R GSS variant is the presence of PrP217-containing amyloid deposits and neurofibrillary degeneration in the brain tissue (10 )
- In a previous study carried out on a transfected neuroblastoma cell model of GSS Q217R , we showed that a significant proportion of PrP217 , which we identified as PrP32 , retains the anchor C-terminal signal peptide , fails to acquire the glycosyl phosphatidylinositol (GPI) anchor , and is retained in the ER by the cellular quality control system
- Transfected M17 cells expressing wild type or mutant prion protein (Q217R) were generated as described (9 )
- Combined , these experiments clearly show that the 32-kDa band recovered following immunoprecipitation with antibodies to KDEL contains PrP32 and that PrP32 is associated with BiP in the Q217R transfected neuroblastoma cells
- BiP interaction with the PrP carrying the Q217R mutation is more complex
- The second variant , PrP32 , which accounts for approximately 11% of the total Q217R mutant PrP , is glycosylated but lacks the GPI anchor and carries the uncleaved GPI anchor signal peptide (9 )
- For example , the different BiP binding might be related to intrinsic conformational differences between the two Q217R PrP variants
- Regardless of the mechanism , it is remarkable that two major types of Q217R mutant PrP , PrP217 and PrP32 , interact differently with BiP , and after this interaction , are processed through different routes
- Thus , each of the two forms of Q217R mutant PrP has the potential to perturb the cellular metabolism , but by distinct mechanisms
- In conclusion , the present finding , that the two mutant PrP variants generated by the Q217R PRNP mutation are processed through entirely different metabolic pathways , underscores the complexity and diversity of the pathogenic perturbation that may be caused by a simple point mutation
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Reference #5 (Tagliavini F et al.): Q217R
- INTRODUCTION (image)TOP (image)ABSTRACT (image)INTRODUCTION (image)EXPERIMENTAL PROCEDURES (image)RESULTS (image)DISCUSSION (image)REFERENCES Gerstmann-Sträussler-Scheinker disease (GSS)1 is an adult-onset neurodegenerative disorder (1 , 2 ) that is inherited as an autosomal dominant trait and segregates with variant genotypes resulting from the combination of a pathogenic mutation (P102L , P105L , A117V , F198S , D202N , Q212P , and Q217R) and a common polymorphism at codon 129 (Met / Val) in the prion protein (PrP) gene (PRNP) (3-9 )
- In previous studies we have determined the biochemical composition of amyloid fibrils extracted from brain tissue of patients with mutations F198S and Q217R in PRNP
- Notably , the degree of protease resistance of this peptide was lower than that of other GSS mutant proteins since , unlike analogous fragments from patients with F198S and Q217R PrP variants , it was completely degraded in the presence of SDS
- Similar to previous studies on GSS F198S and Q217R , this fragment was derived from the mutant allele since only Val was found at position 117 and 129 (18 )
- The top diagram illustrates the polypeptide chain of mature human PrP with the octapeptide repeat region , the common Met / Val polymorphism at codon 129 , and the mutations A117V , F198S , and Q217R associated with GSS
- The first four PrP fragments correspond to amyloid peptides isolated from four GSS patients with F198S , Q217R , and A117V (present case) mutation
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Reference #6 (Piccardo P et al.): Q217R
- 3 GSS is caused by mutations P102L , P105L , A117V , G131V , F198S , D202N , Q212P , and Q217R in PRNP
- 32 Further analysis showed that the smallest amyloid subunit in GSS F198S and GSS Q217R corresponds to a 7-kd fragment comprising residues W81 to Y150 and W81 to E146 , respectively.16 In addition , preliminary data on a patient of an American family with GSS A117V showed a similar fibrillogenic fragment with a ragged N terminus corresponding to W81 , G82 , and Q83 and the C terminus at E146.17 Thus , patients with these GSS variants may accumulate amyloid subunits of similar size and primary structure , despite the different genotypes and phenotypic presentations
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Reference #7 (Ivanova L et al.): Q217R
- Using immunofluorescence techniques , Singh and colleagues (17 , 20 ) found that human PrP carrying a Q217R mutation , linked to Gerstmann-Sträussler syndrome , was expressed at reduced levels on the cell surface and also accumulated in the ER , Golgi , and endosomes / lysosomes
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Reference #8 (Yedidia Y et al.): Q217R
- The stop codon mutant Y145stop and the mutant Q217R are both associated with Gerstmann-Sträussler-Scheinker syndrome (GSS) , a familial TSE
- In contrast to the complete failure of Y145stop to exit the ER by vesicular traffic , most Q217R molecules are successfully exported down the secretory pathway
- A minority of Q217R molecules , however , is retained in the ER , where it interacts with BiP for an unusually long time , and is then degraded by the proteasome pathway (Jin et al. , 2000 )
- In the case of the unstable PrP mutant Q217R , interaction with BiP has been demonstrated (Jin et al. , 2000 )
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Reference #9 (Ma J et al.): Q217R
- However , detailed studies of the fate of two PrP mutants , Q217R and Y145stop , indicate that they accumulate in the ER and other membrane-bound compartments when proteasome activity is blocked (14 , 15 )
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Reference #10 (Mastrangelo P et al.): Q217R
- Since the remaining GSS mutations (G131V , H178R , F198S , D202N , Q212P and Q217R) do not result in the creation of amino acid residues that are also conserved in Dpl , the hypothesis that GSS PRNP alleles result in PrPC molecules more Dpl-like than wt PrPC was rejected
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Reference #11 (Roucou X et al.): Q217R
- Furthermore , wild-type and mutant PrPs , Y145stop and Q217R , respectively , generate intracellular PrP in the presence of proteasome inhibitors , indicating that the normally secreted PrP is subject to the degradative pathway termed endoplasmic reticulum associated protein degradation (ERAD) , possibly to eliminate misfolded PrP molecules (2 -5 )
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Reference #12 (Apetri AC et al.): Q217R
- All variants containing mutations linked to familial prion diseases (P102L , D178N with 129M and 129V polymorphism , V180I , F198S , E200K , R208H , V210I , and Q217R) were constructed on the background of W99F / Y218W huPrP-(90-231) (21 ) by site-directed mutagenesis using appropriate primers and the QuikChange kit (Stratagene)
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Reference #13 (De Simone A et al.): Q217R
- molecular dynamics | prion protein | PrP Q217R mutation | solvent entropy | protein solvation ------------------------------------------------------------------------ Globular proteins or the soluble domains of membrane proteins have evolved in an aqueous environment , and therefore , protein-water interactions have an essential role in defining their folding and their general properties
- We also studied the structural and solvation consequences of a pathogenic point mutation associated with Gerstmann-Straussler-Scheinker disease (Q217R) because our data suggest that it is linked to one of the structurally conserved waters
- Effects of the Q217R Mutation on Site1
- Q217R mutation
- (B) Effect of Q217R mutation on the local MD simulated structure , with relative structural rearrangements in the pocket
- In the calculations , there are conformational rearrangements arising from the mutation Q217R that lead to an elongation of the beta -strand
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Reference #14 (Singh N et al.): Q217R
- We developed a cell model of Gerstmann-Sträussler-Scheinker disease , a neurodegenerative condition characterized by PrP M-containing amyloid deposits and neuronal loss , by expressing the Gerstmann-Sträussler-Scheinker haplotype Q217R-129V in human neuroblastoma cells
- The Q217R-129V haplotype , which segregates with GSS , is associated with a phenotype characterized by prominent PrP deposits , often with the characteristics of amyloid , which contain PrP res forms of all sizes but especially N-terminal and C-terminal truncated forms (13 )
- In this study we report on the metabolism of the PrP M expressed in cells transfected with the Q217R-129V PRNP construct
- Human neuroblastoma cells (M17) expressing normal (Q217-129V) or mutant (Q217R-129V) PrP were generated as described (15 )
- To explore this possibility , Q217R and wild type-transfected cells were labeled either with [35S]methionine and -cysteine (tran35S-label) (Fig. 5 , lanes 1 and 2) or [3H]ethanolamine (Fig. 5 , lanes 3 and 4) , which labels the GPI anchor
- ------------------------------------------------------------------------ DISCUSSION (image) The complex changes in the biogenesis of PrP M induced by the Q217R-129V genotype show that a PRNP point mutation affects the metabolism of human PrP M in significant ways as was previously shown for the D178N mutation (15 )
- Effects of the Q217R-129V Genotype on the Biogenesis of PrP M Although synthesis and maturation of full-length PrP M are similar to those of PrP C , aberrant PrP M forms are detected soon thereafter , and the the full-length PrP M forms undergo surprising posttranslational changes
- The Q217R mutation also destabilizes the full-length PrP M forms , the majority of which aggregate , whereas a small amount may undergo degradation
- The PK-resistant fragments generated by the exogenous protease in the Q217R mutant cells , as in the PrP Res present in prion diseases , lacks the N terminus (data not shown)
- Collectively these findings indicate that the primary effect of the Q217R-129V genotype is a perturbation of the PrP M conformation
- The Q217R Cell Model and the Q217R Human Prion Disease The presence of a 7-kDa internal peptide spanning from residues 81 / 82 to residues 145 / 146 has been demonstrated in amyloid deposits from brains of affected subjects carrying the Q217R-129V haplotype (13 )
- However , the Q217R cell model and the human disease differ in two major ways as follows: 1) the degree of resistance to PK of the protease-resistant PrP M in the mutant cells is at most modest , and 2) the transfected cells apparently lack the above-mentioned 7-kDa internal PrP M fragment found in the brain
- The Q217R Cell Model and Other Cell Models of Prion and Nonprion Diseases The only clear similarity between the Q217R cell model and that of FFI and CJD178 , two inherited prion diseases genetically linked to the D178N-129M and D178N-129V haplotypes , respectively (15 ) , is the instability of PrP M
- In these studies , which do not focus on the Q217R mutation , the various PrP M glycoforms , including the unglycosylated form , are well represented at the cell surface , are detergent-insoluble and protease-resistant at the plasma membrane , and when at the surface , remain attached to the plasma membrane despite cleavage of the GPI anchor by PI-PLC , suggesting that PrP M itself is tightly associated with the cell membrane
- The Q217R Mutation: Implications for GPI Anchor Addition and the Quality Control System of the Secretory Pathway Since deletion of amino acid residues in the sequence flanking the N-terminal side of the acceptor residue has not been reported to impair anchoring (34 ) , it is remarkable that a point mutation at residue 217 interferes with the anchor linkage which normally occurs 14 amino acids downstream , at residue 231
- The aberrant PrP M forms caused by the Q217R mutation appear to be variously affected by the quality control system
- The Q217R neuroblastoma cells thus provide a striking model of the complex changes that a PRNP point mutation can introduce into the processing of PrP M , presumably engendering various degrees of protein misfolding
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Reference #15 (Parchi P et al.): Q217R
- In contrast , purified amyloid preparations from GSS affected subjects carrying the Y145STOP , F198S , A117V , or Q217R mutations were shown to contain PrP-res fragments of 11 and 7 kDa with ragged N and C termini (6 , 7 )
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Reference #16 (Riek R et al.): Q217R
- Close-ups of individual mutation sites: (a) D178N and T183A , (b) Q217R , (c) F198S , and (d) V180I and V210I
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2005, PrionDB.
cmbi.ru.nl), 22-Aug-2005