Rare structural genetic variation in human prion diseases

Lukić, Ana; Uphill, James; Brown, Craig; Beck, John S.; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E.; Collinge, John; Mead, Simon

doi:10.1016/j.neurobiolaging.2015.01.011

Cited by 6 publications

(4 citation statements)

References 41 publications

(62 reference statements)

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“…Prion diseases, such as human prion diseases, are a group of progressive neurodegenerative disorders caused by conformational conversion of the α-helix-rich isoform of the prion protein (PrP C ), which is the normal form, into the β-sheet rich isoform (PrP Sc ), which is the disease-associated form [1,149,150]. Abnormal folding of the protein (PrP Sc ) leads to brain damage and causes high fatality rates in both humans and animals [151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166]. However, the pathogenic mechanism that triggers this abnormal folding leading to prion diseases remains unknown.…”

Section: Prion Diseasementioning

confidence: 99%

Using NMR spectroscopy to investigate the role played by copper in prion diseases

et al. 2020

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Prion diseases are a group of rare neurodegenerative disorders that develop as a result of the conformational conversion of normal prion protein (PrP C) to the disease-associated isoform (PrP Sc). The mechanism that actually causes disease remains unclear. However, the mechanism underlying the conformational transformation of prion protein is partially understood-in particular, there is strong evidence that copper ions play a significant functional role in prion proteins and in their conformational conversion. Various models of the interaction of copper ions with prion proteins have been proposed for the Cu (II)-binding, cell-surface glycoprotein known as prion protein (PrP). Changes in the concentration of copper ions in the brain have been associated with prion diseases and there is strong evidence that copper plays a significant functional role in the conformational conversion of PrP. Nevertheless, because copper ions have been shown to have both a positive and negative effect on prion disease onset, the role played by Cu (II) ions in these diseases remains a topic of debate. Because of the unique properties of paramagnetic Cu (II) ions in the magnetic field, their interactions with PrP can be tracked even at single atom resolution using nuclear magnetic resonance (NMR) spectroscopy. Various NMR approaches have been utilized to study the kinetic, thermodynamic, and structural properties of Cu (II)-PrP interactions. Here, we highlight the different models of copper interactions with PrP with particular focus on studies that use NMR spectroscopy to investigate the role played by copper ions in prion diseases.

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Section: Prion Diseasementioning

confidence: 99%

Using NMR spectroscopy to investigate the role played by copper in prion diseases

et al. 2020

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“…89 Furthermore, a more recent study did not observe any association with the rare occurrence of PRNP gene duplication with sporadic CJD disease incidence. 90 While a number of genomic regions are associated with a variety of prion diseases, the effect of these regions is considered modest and to date the prion gene itself is the strongest risk factor across human prion diseases, though interestingly, some of genomic regions associated with the occurrence of vCJD overlap with syntenic regions identified in animal studies. Although this may be purely coincidental, it is certainly noteworthy given the cross-species applicability of BSE and vCJD.…”

Section: Disease Association Linked To Genes Other Than Prnpmentioning

confidence: 99%

Genetics of Prion Disease in Cattle

Murdoch

2015

Bioinform Biol Insights

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Bovine spongiform encephalopathy (BSE) is a prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. As a transmissible disease of livestock, it has impacted food safety, production practices, global trade, and profitability. Genetic polymorphisms that alter the prion protein in humans and sheep are associated with transmissible spongiform encephalopathy susceptibility or resistance. In contrast, there is no strong evidence that nonsynonymous mutations in the bovine prion gene (PRNP) are associated with classical BSE (C-BSE) disease susceptibility, though two bovine PRNP insertion/deletion polymorphisms, in the putative region, are associated with susceptibility to C-BSE. However, these associations do not explain the full extent of BSE susceptibility, and loci outside of PRNP appear to be associated with disease incidence in some cattle populations. This article provides a review of the current state of genetic knowledge regarding prion diseases in cattle.

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“…Third, differences in risk of prion disease by sex, age, and codon 129 genotype do not appear to be explained by different levels of PRNP expression 25 . Fourth, duplication of the PRNP locus would be predicted to increase risk of CJD by causing overexpression, but this has only been reported once in a control individual 26 . Overall, more routine sequencing of the non-coding regions of PRNP in CJD patients may provide insights into regulatory variants and risk of disease.…”

Section: Introductionmentioning

confidence: 99%

Prion protein gene mutation detection using long-read Nanopore sequencing

Kroll

Dimitriadis

Campbell

et al. 2022

Sci Rep

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Prion diseases are fatal neurodegenerative conditions that affect humans and animals. Rapid and accurate sequencing of the prion gene PRNP is paramount to human prion disease diagnosis and for animal surveillance programmes. Current methods for PRNP genotyping involve sequencing of small fragments within the protein-coding region. The contribution of variants in the non-coding regions of PRNP including large structural changes is poorly understood. Here, we used long-range PCR and Nanopore sequencing to sequence the full length of PRNP, including its regulatory region, in 25 samples from blood and brain of individuals with inherited or sporadic prion diseases. Nanopore sequencing detected the same variants as identified by Sanger sequencing, including repeat expansions/deletions. Nanopore identified additional single-nucleotide variants in the non-coding regions of PRNP, but no novel structural variants were discovered. Finally, we explored somatic mosaicism of PRNP’s octapeptide repeat region, which is a hypothetical cause of sporadic prion disease. While we found changes consistent with somatic mutations, we demonstrate that they may have been generated by the PCR. Our study illustrates the accuracy of Nanopore sequencing for rapid and field prion disease diagnosis and highlights the need for single-molecule sequencing methods for the detection of somatic mutations.

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Rare structural genetic variation in human prion diseases

Cited by 6 publications

References 41 publications

Using NMR spectroscopy to investigate the role played by copper in prion diseases

Using NMR spectroscopy to investigate the role played by copper in prion diseases

Genetics of Prion Disease in Cattle

Prion protein gene mutation detection using long-read Nanopore sequencing

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