Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells

Kanata, Ειrini; Arsenakis, Minas; Sklaviadis, Theodoros

doi:10.1080/19336896.2016.1199312

Cited by 3 publications

(4 citation statements)

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“…Similar to sheep, some caprine PRNP codon variants (G32stop, G127S, I142M, H143R, N146S/D, R154H, R211Q, and Q222K) were associated with different levels of resistance to TSE [3,[5][6][7][8]14,15,[17][18][19][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. However, the most promising results have been obtained for variant K222, which was reported as conferring resistance in Italian goats [17,18].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in the Prion Protein Gene (PRNP) of Two Tunisian Goat Populations

Kdidi

Yahyaoui

Conte

et al. 2021

Animals

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Scrapie is a fatal prion disease. It belongs to transmissible spongiform encephalopathies (TSEs), and occurs in sheep and goats. Similarly, to ovine species, the prion protein gene (PRNP) plays a major role in conferring resistance or susceptibility to TSE in goats. This study assesses the variability of PRNP in native and crossed-breed goat populations raised in the Southeast of Tunisia and provides information on the distribution of PRNP haplotypes and genotypes in these goat populations. A total of 116 unrelated goats including 82 native and 34 crossed-breed goats were screened for PRNP polymorphisms using Sanger sequencing. Sequence analysis revealed 10 non-synonymous polymorphisms (G37V, M137I, R139S, I142M, H143R, N146D, R154H, R211Q, Q222K, and S240P), giving rise to 12 haplotypes and 23 genotypes. Moreover, four silent mutations were detected at codons 30, 42, 138, and 179; the former was reported for the first time in goat (nucleotide 60 c→t). Interestingly, the PrP variants associated with resistance (D146 and K222) or with a prolonged incubation time of goat to scrapie (M142, R143, H154, Q211) were absent or detected with low frequencies except for H154 variant, which is present with high frequency (1%, 1%, 4%, 0%, 88%, and 6%, respectively, for native goats, and 0%, 1%, 0%, 1%, 78%, and 1%, respectively, for crossed goats). The analysis of PRNP polymorphisms of goats raised in other regions of the country will be useful in getting a global view of PRNP genetic variability and the feasibility of goat breeding programs in Tunisia.

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Section: Introductionmentioning

confidence: 99%

Genetic Variation in the Prion Protein Gene (PRNP) of Two Tunisian Goat Populations

Kdidi

Yahyaoui

Conte

et al. 2021

Animals

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“…scrapie challenge was also observed; three animals died after very long incubation periods of approximately 5.5 years (Lacroux et al., ). Secondly, in vitro studies demonstrated a failure of prion conversion with the K222 PrP protein using one common scrapie strain (Eiden et al., ), although successful conversion of K222 PrP protein with another scrapie strain using a different in vitro assay may indicate strain sensitivity in this process (Kanata et al., ). Bioassays using transgenic mice expressing only K222 (equivalent to homozygous goat KK222 genotype) were resistant to challenge with six different scrapie isolates, and partial resistance was demonstrated by mice expressing K222 combined with wild type Q222 (approximating the caprine heterozygous genotype QK222) which succumbed to two out of four scrapie isolates.…”

Section: Assessmentmentioning

confidence: 99%

“…challenge (after very extended inc. time) • 2 out 9 QK222 goats preclinically positive after p.o. challenge with BSE (Fast et al, in press) • One (1 out 9) QK222 carrier with late preclinical signs of infection after oral challenge with bovine BSE; detected as PrP Sc in CNS and psoas muscle (Fast et al, in press) • > 40 months after oral challenge with goat BSE one (1 out 3) QK222 carrier with low infectivity titre detected by bioassay (Aguilar-Calvo et al, 2015) • No significant reduction compared to wt PrP in 22L-scrapie CC (Kanata et al, 2016) • show that prion disease and prion replication cannot happen without PrP expression (Bueler et al, 1994) • No data Against • Occurrence of this allele restricted to Norway (Benestad et al, 2012) • No case-control study data available…”

Section: K222 Formentioning

confidence: 99%

Genetic resistance to transmissible spongiform encephalopathies (TSE) in goats

Ricci¹,

Allende²,

Bolton³

et al. 2017

EFS2

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Breeding programmes to promote resistance to classical scrapie, similar to those for sheep in existing transmissible spongiform encephalopathies (TSE) regulations, have not been established in goats. The European Commission requested a scientific opinion from EFSA on the current knowledge of genetic resistance to TSE in goats. An evaluation tool, which considers both the weight of evidence and strength of resistance to classical scrapie of alleles in the goat PRNP gene, was developed and applied to nine selected alleles of interest. Using the tool, the quality and certainty of the field and experimental data are considered robust enough to conclude that the K222, D146 and S146 alleles both confer genetic resistance against classical scrapie strains known to occur naturally in the EU goat population, with which they have been challenged both experimentally and under field conditions. The weight of evidence for K222 is greater than that currently available for the D146 and S146 alleles and for the ARR allele in sheep in 2001. Breeding for resistance can be an effective tool for controlling classical scrapie in goats and it could be an option available to member states, both at herd and population levels. There is insufficient evidence to assess the impact of K222, D146 and S146 alleles on susceptibility to atypical scrapie and bovine spongiform encephalopathy (BSE), or on health and production traits. These alleles are heterogeneously distributed across the EU Member States and goat breeds, but often at low frequencies (< 10%). Given these low frequencies, high selection pressure may have an adverse effect on genetic diversity so any breeding for resistance programmes should be developed at Member States, rather than EU level and their impact monitored, with particular attention to the potential for any negative impact in rare or small population breeds.

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“…The research question arises: What are reasons allowing the protein of a resistant species to retain its folding? For rabbit normal cellular prion protein (PrP C , where the structural region of a PrP C consists of b-strand 1 (b1), a-helix 1 (a1 or H1), b-strand 2 (b2), a-helix 2 (a2 or H2), a-helix 3 (a3 or H3), and the loops linking them each other), multiple amino acid residues G99, M108, S173, I214, together inhibit formation of its abnormal isoform (Kanata et al, 2016;Vorberg et al, 2003). For dog PrP, D159 is the key protective residue that provides conformational stability and confers protection against prions, suggesting that a single amino acid D159 is sufficient to prevent PrP conformational change and pathogenesis (Sanchez-Garcia et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics studies of dog prion protein wild-type and its D159N mutant

Zhang

2020

Journal of Biomolecular Structure and Dynamics

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Prion diseases (e.g. 'mad cow' disease in cattle, chronic wasting disease in deer and elk, Creutzfeldt-Jakob disease in humans) have been a major public health concern affecting humans and almost all animals. However, dogs are strongly resistant to prion diseases. Recently, through transgenic techniques, it was reported that the single (surface) residue D159 is sufficient to confer protection against protein conformational change and pathogenesis, thus provides conformational stability for dog prion protein. This made a big breakthrough in dog prion protein research field. For dog prion protein, another advancement is the produce of its NMR structure in 2005. However, all these breakthroughs are still short of enough structural informatics of dog prion protein. This paper studies dog prion protein wild-type and D159N mutant through molecular dynamics (MD) techniques. Our MD results reveal sufficient structural informatics on the residue at position 159 to understand the mechanism underlying the resistance to prion diseases of dogs. The structural informatics of this paper should be very useful for the medicinal treatment of prion diseases.

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Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells

Cited by 3 publications

References 73 publications

Genetic Variation in the Prion Protein Gene (PRNP) of Two Tunisian Goat Populations

Genetic Variation in the Prion Protein Gene (PRNP) of Two Tunisian Goat Populations

Genetic resistance to transmissible spongiform encephalopathies (TSE) in goats

Molecular dynamics studies of dog prion protein wild-type and its D159N mutant

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