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1.
ABSTRACT. Familial fatal insomnia (FFI) is fatal disorder characterized by damage to select thalamic nuclei, together with progressive insomnia and dysautonomia. In subjects carrying the D178N prion protein (PRNP) mutation, distinct phenotypes can be observed, depending on the methionine (Met) /valine (Val) codon 129 polymorphism. We report here a Chinese case of FFI with a D178N/Met129 genotype of the PRNP gene, who exhibited rapidly progressive dementia combined with behavioral disturbances and paroxysmal limb myoclonus. Our patient did not show refractory insomnia early in the disease course, nor demonstrate typical MRI and EEG alterations. There was remarkable family history of similar symptoms.KEYWORDS: D178N, Familial fatal insomnia, Met129, prion protein 相似文献
2.
《朊病毒》2013,7(3):228-235
ABSTRACT. Familial fatal insomnia (FFI) is fatal disorder characterized by damage to select thalamic nuclei, together with progressive insomnia and dysautonomia. In subjects carrying the D178N prion protein (PRNP) mutation, distinct phenotypes can be observed, depending on the methionine (Met) /valine (Val) codon 129 polymorphism. We report here a Chinese case of FFI with a D178N/Met129 genotype of the PRNP gene, who exhibited rapidly progressive dementia combined with behavioral disturbances and paroxysmal limb myoclonus. Our patient did not show refractory insomnia early in the disease course, nor demonstrate typical MRI and EEG alterations. There was remarkable family history of similar symptoms. 相似文献
3.
Robert B. Petersen Lev G. Goldfarb Massimo Tabaton Paul Brown Lucia Monari Pietro Cortelli Pasquale Montagna Lucila Autilio-Gambetti D. Carleton Gajdusek Elio Lugaresi Pierluigi Gambeffi 《Molecular neurobiology》1994,8(2-3):99-103
Fatal familial insomnia (FFI) is a subacute dementing illness originally described in 1986. The phenotypic characteristics
of this disease include progressive untreatable insomnia, dysautonomia, endocrine and motor disorders, preferential hypometabolism
in the thalamus as determined by PET scanning, and selective thalamic atrophy. These characteristics readily distinguish FFI
from other previously described neurodegenerative conditions. Recently, FFI was shown to be linked to a mutation in the prion
protein gene (PRNP) at codon 178, which results in the substitution of asparagine for aspartic acid. As such, FFI represents
the most recent addition to the growing family of prion protein-related diseases. The mutation that results in FFI had previously
been linked to a subtype of familial Creutzfeld-Jakob disease (178Asn CJD). The genotypic basis for the difference between FFI and 178AsnCJD lies in a polymorphism at codon 129 of the mutant prion protein gene: 129Met 178Asn results in FFI, 129Val 178Asn in CJD. The finding that the combination of a polymorphism and a single pathogenic mutation result in two distinct conditions
represents a singnificant advance in our understanding of phenotypic variability. 相似文献
4.
One of the arguments in favor of the protein-only hypothesis of transmissible spongiform encephalopathies is the link between inherited prion diseases and specific mutations in the PRNP gene. One such mutation (Asp178 --> Asn) is associated with two distinct disorders: fatal familial insomnia or familial Creutzfeldt-Jakob disease, depending upon the presence of Met or Val at position 129, respectively. In this study, we have characterized the biophysical properties of recombinant human prion proteins (huPrP90-231) corresponding to the polymorphic variants D178N/M129 and D178N/V129. In comparison to the wild-type protein, both polymorphic forms of D178N huPrP show a greatly increased propensity for a conversion to beta-sheet-rich oligomers (at acidic pH) and thioflavine T-positive amyloid fibrils (at neutral pH). Importantly, the conversion propensity for the D178N variant is strongly dependent upon the M/V polymorphism at position 129, whereas under identical experimental conditions, no such dependence is observed for the wild-type protein. Amyloid fibrils formed by wild-type huPrP90-231 and the D178N variant are characterized by different secondary structures, and these structures are further modulated by residue 129 polymorphism. Although on the basis of only in vitro data, this study strongly suggests that polymorphism-dependent phenotypic variability of familial prion diseases may be linked to differences in biophysical properties of prion protein variants. 相似文献
5.
《Seminars in Virology》1996,7(3):181-187
Major advances have been made in the understanding of the molecular basis of phenotypic variability in human prion diseases over the last few years. Strong evidence indicates that a complex interaction between specific mutations and the polymorphic codon 129 of the prion protein gene (PRNP) underlies the genetic control of phenotypic expression in familial human prion diseases. Fatal familial insomnia (FFI) and a subtype of familial CJD (CJD178), two prion diseases with different clinico-pathological features, the same mutation at codon 178 ofPRNPbut a different amino acid at codon 129 of the mutantPRNPallele, represent the best characterized example of this complex interplay between thePRNPgenotype and phenotypic variability. Protein studies have subsequently shown that the different genotype of the mutant allele in FFI and CJD178results in the formation of two different protease-resistant prion proteins (PrPres) which differ in size and glycosylation. These biochemical characteristics of PrPresas well as differences among distinct brain regions in the timing and rate of PrPresdeposition and in the vulnerability to PrPresalso appear to be major determinants of phenotypic expression in human prion diseases. 相似文献
6.
Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are associated to the same mutation at codon 178 but differentiate into clinicopathologically distinct diseases determined by this mutation and a naturally occurring methionine-valine polymorphism at codon 129 of the prion protein gene. It has been suggested that the clinical and pathological difference between FFI and CJD is caused by different conformations of the prion protein. Using molecular dynamics (MD), we investigated the effect of the mutation at codon 178 and the polymorphism at codon 129 on prion protein dynamics and conformation at normal and elevated temperatures. Four model structures were examined with a focus on their dynamics and conformational changes. The results showed differences in stability and dynamics between polymorphic variants. Methionine variants demonstrated a higher stability than valine variants. Elongation of existing beta-sheets and formation of new beta-sheets was found to occur more readily in valine polymorphic variants. We also discovered the inhibitory effect of proline residue on existing beta-sheet elongation. 相似文献
7.
Ihssane Bouybayoune Susanna Mantovani Federico Del Gallo Ilaria Bertani Elena Restelli Liliana Comerio Laura Tapella Francesca Baracchi Natalia Fernández-Borges Michela Mangieri Cinzia Bisighini Galina V. Beznoussenko Alessandra Paladini Claudia Balducci Edoardo Micotti Gianluigi Forloni Joaquín Castilla Fabio Fiordaliso Fabrizio Tagliavini Luca Imeri Roberto Chiesa 《PLoS pathogens》2015,11(4)
Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. 相似文献
8.
Lev G. Goldfarb Paul Brown Larisa Cervenakova D. Carleton Gajdusek 《Molecular neurobiology》1994,8(2-3):89-97
Genetic study of over 200 cases of Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and kuru have brought a reliable body of evidence that the familial forms of CJD and all known cases of GSS and FFI are linked to germline mutations in the coding region of the PRNP gene on chromosome 20, either point substitutions or expansion of the number of repeat units. No pathogenic mutations have so far been found in sporadic or infectious forms of CJD, although there are features of genetic predisposition in iatrogenic CJD and kuru. In FFI and familial CJD, clinically and pathologically distinct syndromes that are both linked to the 178Asp→Asn substitution, phenotypic expression is dependent on a polymorphism at codon 129. Synthetic peptides homologous to several regions of PrP spontaneously form insoluble amyloid fibrils with unique morphological characteristics and polymerization tendencies. Peptides homologous to mutated regions of PrP exhibit enhanced fibrilogenic properties and, if mixed with the wild-type peptide, produce even more abundant and larger fibrous aggregates. A similar process in vivo may lead to amyloid accumulation and disease, and transmission of “baby fibrils” may induce disease in other hosts. 相似文献
9.
Intra- and interspecies interactions between prion proteins and effects of mutations and polymorphisms 总被引:4,自引:0,他引:4
Recently, crystallization of the prion protein in a dimeric form was reported. Here we show that native soluble homogeneous FLAG-tagged prion proteins from hamster, man and cattle expressed in the baculovirus system are predominantly dimeric. The PrP/PrP interaction was confirmed in Semliki Forest virus-RNA transfected BHK cells co-expressing FLAG- and oligohistidine-tagged human PrP. The yeast two-hybrid system identified the octarepeat region and the C-terminal structured domain (aa90-aa230) of PrP as PrP/PrP interaction domains. Additional octarepeats identified in patients suffering from fCJD reduced (wtPrP versus PrP + 9OR) and completely abolished (PrP + 9OR versus PrP + 9OR) the PrP/PrP interaction in the yeast two-hybrid system. In contrast, the Met/Val polymorphism (aa129), the GSS mutation Pro102Leu and the FFI mutation Asp178Asn did not affect PrP/PrP interactions. Proof of interactions between human or sheep and bovine PrP, and sheep and human PrP, as well as lack of interactions between human or bovine PrP and hamster PrP suggest that interspecies PrP interaction studies in the yeast two-hybrid system may serve as a rapid pre-assay to investigate species barriers in prion diseases. 相似文献
10.
Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport. 相似文献
11.
The risk of acquiring variant Creutzfeldt-Jakob disease is closely related to polymorphism at codon 129 of the human prion gene, because almost all variant Creutzfeldt-Jakob disease patients are Met/Met homozygotes. Although animal transmission experiments corroborated this seeding discrimination, the origin of the differential seeding efficiency of the bovine prion seed for human codon 129 polymorphism remained elusive. Here, we used a short prion protein (PrP) peptide as a model system to test whether seeding discrimination can be found in this simple system. We used a previously developed 'seed-titration method' and time-resolved CD spectroscopy to compare sequence-dependent seeding efficiency regarding codon 129 polymorphism. Our results showed that the Met→Val substitution on the human PrP (huPrP) peptide decreased seeding efficiency by 10 times when fibrils formed from bovine PrP (bPrP) peptide were used as the seed. To explore whether the different seeding barrier is due to the chemical and structural properties of Met and Val or whether another residue is involved in this peptide model, we constructed three bPrP mutants, V112M, L138I and N143S, in each of which one residue was replaced by the corresponding human residue. Our data showed that Leu138 in the bPrP seed might be the key residue causing the different seeding efficiencies related to 129M/V polymorphism and the interference effect of huPrP129V in the huPrP129M/V mixture. We propose a 'surface competition hypothesis' to explain the big seeding barrier caused by 129V in the PrP peptide seeding experiment. 相似文献
12.
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 《The Journal of biological chemistry》2001,276(8):6009-6015
Gerstmann-Str?ussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val(129) being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a approximately 7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the approximately 7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Str?ussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a approximately 7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation. 相似文献
13.
Asano M Mohri S Ironside JW Ito M Tamaoki N Kitamoto T 《Biochemical and biophysical research communications》2006,342(1):293-299
Variant Creutzfeldt-Jakob disease (vCJD) appears to be caused by infection with the bovine spongiform encephalopathy (BSE) agent. To date, all patients with vCJD are homozygous for methionine at codon 129 of the PrP gene. To investigate the relationship between polymorphism at codon 129 and susceptibility to BSE or vCJD prions, we performed splenic follicular dendritic cell assay with humanized knock-in mice through peripheral infection. All humanized knock-in mice showed little or no susceptibility to BSE prions. Only the subset of humanized knock-in mice with codon 129 Met/Met genotype showed weak susceptibility by Western blotting. Surprisingly, we succeeded in the transmission of vCJD prions to humanized knock-in mice not only with codon 129 Met/Met but also with codon 129 Met/Val. Humanized knock-in mice with codon 129 Val/Val were not susceptible. The results suggest that human heterozygotes at codon 129 are also at risk for secondary infection with vCJD. 相似文献
14.
Garmy N Guo XJ Taïeb N Tourrès C Tamalet C Fantini J Yahi N 《Cell biology international》2006,30(6):559-567
The cellular isoform of the normal prion protein PrP(c), encoded by the PRNP gene, is expressed in human intestinal epithelial cells where it may represent a potential target for infectious prions. We have sequenced the PRNP gene in Caco-2 and HT-29 parental and clonal cell lines, and found that these cells have a distinct polymorphism at codon 129. HT-29 cells are homozygous Met/Met, whereas Caco-2 cells are heterozygous Met/Val. The 129Val variant was also detected in Caco-2 mRNAs. Real-time PCR quantifications revealed that PrP(c) mRNAs were more expressed in HT-29 cells than in Caco-2 cells. These data were confirmed by studying the expression of PrP(c) in plasma membranes and lipid rafts prepared from these cells. Overall, these results may be important in view of using human intestinal cell lines Caco-2 and HT-29 as cellular in vitro models to study the initial steps of prion propagation after oral inoculation. 相似文献
15.
Marcin I. Apostol Michael R. Sawaya Duilio Cascio David Eisenberg 《The Journal of biological chemistry》2010,285(39):29671-29675
A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are “steric zippers,” pairs of interacting β-sheets. Both structures of these “homozygous steric zippers” reveal direct intermolecular interactions between Met or Val in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression. 相似文献
16.
Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD). 总被引:7,自引:1,他引:6
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R Gabizon H Rosenmann Z Meiner I Kahana E Kahana Y Shugart J Ott S B Prusiner 《American journal of human genetics》1993,53(4):828-835
The inherited prion diseases are neurodegenerative disorders which are not only genetic but also transmissible. More than a dozen mutations in the prion protein gene that result in nonconservative amino acid substitutions segregate with the inherited prion diseases including familial Creutzfeldt-Jakob disease (CJD). In Israel, the incidence of CJD is about 1 case/10(4) Libyan Jews. A Lys200 substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of > 4.8. Some healthy elderly Lys200 carriers > age 65 years were identified, suggesting the possibility of incomplete penetrance. In contrast, no linkage was found between the development of familial CJD and a polymorphism encoding either Met129 or Val129. All Libyan Jewish CJD patients with the Lys200 mutation encode a Met129 on the mutant allele. Homozygosity for Met129 did not correlate with age at disease onset or the duration of illness. The frequency of the Met129 allele was higher in the affected pedigrees than in a control population of Libyan Jews. The frequency of the Met129 and Val129 alleles in the control Libyan population was similar to that found in the general Caucasian population. The identification of three Libyan Jews homozygous for the Lys200 mutation suggests frequent intrafamilial marriages, a custom documented by genealogical investigations. 相似文献
17.
Tahiri-Alaoui A Gill AC Disterer P James W 《The Journal of biological chemistry》2004,279(30):31390-31397
The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of beta-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences in the folding behavior between the two variants at the early stages of oligomer formation. We show that Met(129) has a higher propensity to form beta-sheet-rich oligomers, whereas Val(129) has a higher tendency to fold into alpha-helical-rich monomers. An equimolar mixture of both variants displayed an intermidate folding behavior. We show that the oligomers of both variants are initially a mixture of alpha- and beta-rich conformers that evolve with time to an increasingly homogeneous beta-rich form. This maturation process, which involves no further change in proteinase K resistance, occurs more rapidly in the Met(129) form than the Val(129) form. Although the involvement of such beta-rich oligomers in prion pathogenesis is speculative, the misfolding behavior could, in part, explain the higher susceptibility of individuals that are methionine homozygote to both sporadic and variant Creutzfeldt-Jakob disease. 相似文献
18.
Mirella Salvatore Maurizio Genuardi Rosella Petraroli Carlo Masullo Marco D'Alessandro Maurizio Pocchiari 《Human genetics》1994,94(4):375-379
Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of the amyloid protein PrP in the CNS. Two coding polymorphisms of the PrP gene (PRNP) are a methionine (Met) to valine (Val) change at codon 129, and a deletion in the octapeptide coding region. In the United Kingdom, homozygosity at codon 129 appears to be associated with a predisposition to develop CJD. However, in Japan, where allelic frequencies and genotype distribution are significantly different, such an association has not been demonstrated. To determine whether such deletion(s) or codon 129 polymorphisms of PRNP predispose to the development of CJD in Italian patients, 31 sporadic CJD patients with no known PRNP mutations, and 186 unrelated control subjects were studied. Genotypic frequencies at codon 129 in these Italian CJD patients revealed a significant excess of methionine alleles, and a different genotype distribution in comparison with the normal Italian population. Deletions of a 24-bp segment located in the PrP octapeptide coding region were found in two control subjects, but in none of the sporadic CJD patients. These data suggest that Met homozygosity at codon 129 may contribute, with other enviromental or endogenous factors, to CJD development. 相似文献
19.
Molecular genetics of human prion diseases in Germany 总被引:12,自引:0,他引:12
Windl O Giese A Schulz-Schaeffer W Zerr I Skworc K Arendt S Oberdieck C Bodemer M Poser S Kretzschmar HA 《Human genetics》1999,105(3):244-252
Human prion diseases may be acquired as infectious diseases, they may be inherited in an autosomal dominant fashion or occur sporadically. Mutations and polymorphisms in the sequence of the coding region of the prion protein gene (PRNP) have been established as an important factor in all of these three types of prion diseases. Therefore, a total of 578 patients with suspect prion diseases referred to the German Creutzfeldt-Jakob disease (CJD) surveillance unit over a period of 4.5 years have been examined for mutations and polymorphisms in the coding region of PRNP. We found 40 cases with a missense mutation previously reported as pathogenic. Amongst these, the aspartate to asparagine change at codon 178 (D178N) was the most common mutation. All of these cases carried the D178N mutation in coupling with methionine at codon 129, resulting in the typical fatal familial insomnia (FFI) genotype. Most cases with pathogenic mutations were not found in the group of clinically "probable" cases according to established clinical criteria, supporting the notion that inherited prion diseases often exhibit atypical features. Two novel missense mutations (T188R and P238S) and several silent polymorphisms were found, demonstrating the quality of our screening procedure based on a modified version of the single-stranded conformational polymorphism technique. In "definite" CJD cases with no pathogenic mutation, the patients clinically classified as "probable" were mostly homozygous for methionine at the common polymorphism at codon 129, whereas there was a marked over-representation of patients homozygous for valine amongst those clinically classified as "possible". This large study on suspect cases of human prion diseases in Germany clearly shows that PRNP genetics is essential for a comprehensive analysis of prion diseases. 相似文献
20.
《Seminars in Virology》1996,7(3):175-180
PrP genotypes of human prion diseases were closely related to deposition types of PrPSc, clinico-pathologic phenotypes and transmission rates to rodents. Wild type CJD with 129M/M, iatrogenic cases, and hereditary CJD with V1801, E200K, and M232R showed synaptic type deposition of PrPSc, similar phenotypes and, except for V1801, similar transmission rates. One patient with fatal familial insomnia transmitted the disease to mice. Plaque type deposition of PrPScinduced various phenotypes, such as GSS or Alzheimer's disease-like dementia, usually with a longer clinical course than CJD. Experimental transmission was positive from one-third of the cases with P102L but negative from other mutation cases with PrP plaques. Polymorphism at codon 129 may modify phenotypes as well as transmission rates. 相似文献