Phenotypic heterogeneity and genetic modifiers in prion disease caused by a Pro102Leu mutation in the PRNP gene

Pathogenic prion protein (PrPSc), converted from normal prion protein (PrPC), causes prion disease. Although prion disease has been reported in several mammalian species, chickens are known to show strong resistance to prion diseases. In addition to chickens, the domestic duck occupies a large proportion in the poultry industry and may be regarded as a potential resistant host against prion disease. However, the DNA sequence of the prion protein gene (PRNP) has not been reported in domestic ducks. Here, we performed amplicon sequencing targeting the duck PRNP gene with the genomic DNA of Pekin ducks. In addition, we aligned the PrP sequence of the Pekin duck with that of various species using ClustalW2 and carried out phylogenetic analysis using Molecular Evolutionary Genetics Analysis X (MEGA X). We also constructed the structural modeling of the tertiary and secondary structures in avian PrP using SWISS-MODEL. Last, we investigated the aggregation propensity on Pekin duck PrP using AMYCO. We first reported the DNA sequence of the PRNP gene in Pekin ducks and found that the PrP sequence of Pekin ducks is more similar to that of geese than to that of chickens and mallards (wild ducks). Interestingly, Pekin duck PrP showed a high proportion of β-sheets compared to that of chicken PrP, and a high aggregation propensity compared to that of avian PrPs. However, Pekin duck PrP with substitutions of chicken-specific amino acids showed reduced aggregation propensities. To the best of our knowledge, this is the first report on the genetic characteristics of the PRNP sequence in Pekin ducks.

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The First Report of Polymorphisms and Genetic Features of the prion-like Protein Gene (PRND) in a Prion Disease-Resistant Animal, Dog

International Journal of Molecular Sciences ◽

10.3390/ijms20061404 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1404 ◽

Cited By ~ 14

Author(s):

Sae-Young Won ◽

Yong-Chan Kim ◽

Kiwon Kim ◽

An-Dang Kim ◽

Byung-Hoon Jeong

Keyword(s):

Linkage Disequilibrium ◽

Prion Disease ◽

Genetic Linkage ◽

Protein Gene ◽

Prnp Gene ◽

Nucleotide Polymorphisms ◽

Direct Dna Sequencing ◽

Disease Resistant ◽

Genetic Features ◽

Resistant Animal

Prion disease has displayed large infection host ranges among several species; however, dogs have not been reported to be infected and are considered prion disease-resistant animals. Case-controlled studies in several species, including humans and cattle, indicated a potent association of prion protein gene (PRNP) polymorphisms in the progression of prion disease. Thus, because of the proximal location and similar structure of the PRNP gene among the prion gene family, the prion-like protein gene (PRND) was noted as a novel candidate gene that contributes to prion disease susceptibility. Several case-controlled studies have confirmed the relationship of the PRND gene with prion disease vulnerability, and strong genetic linkage disequilibrium blocks were identified in prion-susceptible species between the PRNP and PRND genes. However, to date, polymorphisms of the dog PRND gene have not been reported, and the genetic linkage between the PRNP and PRND genes has not been examined thus far. Here, we first investigated dog PRND polymorphisms in 207 dog DNA samples using direct DNA sequencing. A total of four novel single nucleotide polymorphisms (SNPs), including one nonsynonymous SNP (c.149G>A, R50H), were identified in this study. We also found two major haplotypes among the four novel SNPs. In addition, we compared the genotype and allele frequencies of the c.149G>A (R50H) SNP and found significantly different distributions among eight dog breeds. Furthermore, we annotated the c.149G>A (R50H) SNP of the dog PRND gene using in silico tools, PolyPhen-2, PROVEAN, and PANTHER. Finally, we examined linkage disequilibrium between the PRNP and PRND genes in dogs. Interestingly, we did not find a strong genetic linkage between these two genes. To the best of our knowledge, this was the first genetic study of the PRND gene in a prion disease-resistant animal, a dog.

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Age at onset in genetic prion disease and the design of preventive clinical trials

Neurology ◽

10.1212/wnl.0000000000007745 ◽

2019 ◽

Vol 93 (2) ◽

pp. e125-e134 ◽

Cited By ~ 23

Author(s):

Eric Vallabh Minikel ◽

Sonia M. Vallabh ◽

Margaret C. Orseth ◽

Jean-Philippe Brandel ◽

Stéphane Haïk ◽

...

Keyword(s):

Clinical Trials ◽

Prion Disease ◽

Statistical Power ◽

Explanatory Power ◽

Age At Onset ◽

Genetic Modifiers ◽

Trial Duration ◽

Clinical Onset ◽

Subsequent Determination ◽

Prohibitive Cost

ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

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First Report of the Potential Bovine Spongiform Encephalopathy (BSE)-Related Somatic Mutation E211K of the Prion Protein Gene (PRNP) in Cattle

International Journal of Molecular Sciences ◽

10.3390/ijms21124246 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4246 ◽

Cited By ~ 2

Author(s):

Sae-Young Won ◽

Yong-Chan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Somatic Mutation ◽

Prion Disease ◽

In Silico ◽

Somatic Mutations ◽

Protein Gene ◽

Prnp Gene ◽

Spongiform Encephalopathy ◽

Prion Protein Gene

Bovine spongiform encephalopathy (BSE) is a prion disease characterized by spongiform degeneration and astrocytosis in the brain. Unlike classical BSE, which is caused by prion-disease-contaminated meat and bone meal, the cause of atypical BSE has not been determined. Since previous studies have reported that the somatic mutation in the human prion protein gene (PRNP) has been linked to human prion disease, the somatic mutation of the PRNP gene was presumed to be one cause of prion disease. However, to the best of our knowledge, the somatic mutation of this gene in cattle has not been investigated to date. We investigated somatic mutations in a total of 58 samples, including peripheral blood; brain tissue including the medulla oblongata, cerebellum, cortex, and thalamus; and skin tissue in 20 individuals from each breed using pyrosequencing. In addition, we estimated the deleterious effect of the K211 somatic mutation on bovine prion protein by in silico evaluation tools, including PolyPhen-2 and PANTHER. We found a high rate of K211 somatic mutations of the bovine PRNP gene in the medulla oblongata of three Holsteins (10% ± 4.4%, 28% ± 2%, and 19.55% ± 3.1%). In addition, in silico programs showed that the K211 somatic mutation was damaging. To the best of our knowledge, this study is the first to investigate K211 somatic mutations of the bovine PRNP gene that are associated with potential BSE progression.

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Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽

10.3390/pathogens9060482 ◽

2020 ◽

Vol 9 (6) ◽

pp. 482

Author(s):

Simote Foliaki ◽

Bradley Groveman ◽

Jue Yuan ◽

Ryan Walters ◽

Shulin Zhang ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Neurological Disorders ◽

Prion Diseases ◽

Three Dimensional ◽

Protein Isoforms ◽

Genetic Modifiers ◽

Neuronal Tissue ◽

Prion Infection ◽

E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

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Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene

Molecular Brain Research ◽

10.1016/0169-328x(95)00175-r ◽

1995 ◽

Vol 34 (1) ◽

pp. 173-176 ◽

Cited By ~ 64

Author(s):

S. Krasemann ◽

I. Zerr ◽

T. Weber ◽

S. Poser ◽

H. Kretzschmar ◽

...

Keyword(s):

Prion Disease ◽

Prnp Gene

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Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

Brain ◽

10.1093/brain/awn202 ◽

2008 ◽

Vol 131 (10) ◽

pp. 2632-2646 ◽

Cited By ~ 83

Author(s):

T. E. F. Webb ◽

M. Poulter ◽

J. Beck ◽

J. Uphill ◽

G. Adamson ◽

...

Keyword(s):

Prion Disease ◽

Genetic Modification ◽

Phenotypic Heterogeneity

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Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity

Brain ◽

10.1093/brain/awl226 ◽

2006 ◽

Vol 129 (9) ◽

pp. 2297-2317 ◽

Cited By ~ 66

Author(s):

S. Mead

Keyword(s):

Molecular Analysis ◽

Prion Disease ◽

Phenotypic Heterogeneity ◽

Insertional Mutation

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Genetic prion disease: D178N with 129MV disease modifying polymorphism—a clinical phenotype

BMJ Neurology Open ◽

10.1136/bmjno-2020-000074 ◽

2020 ◽

Vol 2 (2) ◽

pp. e000074

Author(s):

Tracie Huey-Lin Tan ◽

Richard J Stark ◽

John A Waterston ◽

Owen White ◽

Dominic Thyagarajan ◽

...

Keyword(s):

Family History ◽

Prion Disease ◽

Neurological Diseases ◽

Prion Diseases ◽

Prnp Gene ◽

Fatal Familial Insomnia ◽

Gene Testing ◽

Positron Emission ◽

Disease Modifying ◽

D178n Mutation

BackgroundHuman prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty.CaseWe present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result.ConclusionPatients with genetic prion disease may have no known family history and normal EEG, MRI brain and CSF findings. PRNP gene testing should be considered for patients with subacute progressive neurological and autonomic dysfunction.

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