Structural and functional analysis of the HSP90AA1 gene: distribution of polymorphisms among sheep with different responses to scrapie

Marcos-Carcavilla, Ane; Calvo, J.H.; Gonzalez, Claudette Hajaj; Moazami‐Goudarzi, Katayoun; Laurent, Pascal; Bertaud, Maud; Hayes, Hélène; Beattie, A. E.; Serrano, Carmen; Lyahyai, Jaber; Martín-Burriel, Inmaculada; Serrano, M.

doi:10.1007/s12192-007-0004-2

Cited by 18 publications

(23 citation statements)

References 43 publications

(46 reference statements)

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“…It codes for a chaperone protein that influences aggregation at early stages in Alzheimer's disease (Evans et al, 2006), induced microglial activation (Kakimura et al, 2002). Moreover, some polymorphisms of the HSP90AA1 gene in the promoter region modulate the gene expression and scrapie resistance in Aragonesa and Romanov sheep breeds (Marcos-Carcavilla et al, 2008). In conclusion, the QTL for scrapie incubation time on chromosome 18 has been confirmed in different PrP genotypes.…”

Section: Discussionmentioning

confidence: 81%

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

Moréno

Moazami‐Goudarzi

Briand

et al. 2009

Journal of General Virology

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Although susceptibility to scrapie is largely controlled by the PrP gene, the role of other genes that affect scrapie resistance in sheep is now confirmed. Following the detection of quantitative trait loci (QTL) on chromosomes 6 and 18 in a half-sib family with an ARQ/VRQ susceptible PrP genotype, the whole pedigree of a naturally infected flock was investigated to confirm these QTL regions in different PrP genotypes. The present study has allowed us to confirm the QTL on chromosome 18, and to demonstrate the QTL effects in several PrP genotypes. INTRODUCTIONScrapie is a transmissible spongiform encephalopathy (TSE), and host resistance is largely controlled by the PrP gene encoding the PrP protein (Goldmann et al., 1990;Palmer et al., 1991). Recently, some loci that modulate susceptibility to TSEs, other than the PrP gene, have been detected in mice (Lloyd et al., 2001(Lloyd et al., , 2002Manolakou et al., 2001;Moreno et al., 2003;Stephenson et al., 2000) and cattle (HernandezSanchez et al., 2002; Zhang et al., 2004). In sheep, Diaz et al. (2005) have shown that the PrP gene explains only part of the total genetic variance of the survival time in a Romanov sheep flock naturally infected by scrapie. Moreno et al. (2008) detected two quantitative trait loci (QTL) regions (at the 5 % chromosome-wide level) affecting scrapie incubation time, on chromosomes 6 and 18, in one half-sib family of 67 scrapie-affected animals.In this article, our aim was to confirm QTL previously detected by Moreno et al. (2008) by using additional data from the sheep population from the INRA Langlade farm and to verify their presence in the PrP genotypes with different scrapie susceptibilities. RESULTSThe significant fixed effects affecting incubation time were the PrP genotype (P,0.001), rearing (P,0.006), litter size (P,0.01), the PrP genotype of dam (P,0.05) and the interaction between season and birth year (P,0.001). The significance of the PrP genotype is mainly due to the greater estimated mean of incubation time for the ARQ/ VRQ genotype compared with the other genotypes (Table 1). However, the standard deviation of the ARQ/ VRQ population was similar to that of the ARQ/ARQ population, but twice that of the VRQ/VRQ population. Because heterogeneous variances were observed between VRQ/VRQ and ARQ/---sub-populations, the variance component analyses were repeated for these two genotype groups separately.The heritabilities of scrapie incubation time estimated in the total population and in sub-populations are shown in Table 2. These heritabilities suggest that, in addition to the PrP effects, a proportion of the between-animal variability is due to genetic effects. However, the estimated values were somewhat (albeit not significantly, P.0.05) higher in the two sub-populations than in the total dataset, particularly when the QTL effect was not fitted.The data provided no evidence of a QTL on chromosome 6, with the likelihood ratio test (LRT) value being close to zero at all tested locations. However, a significant QTL was identified o...

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Section: Discussionmentioning

confidence: 81%

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

Moréno

Moazami‐Goudarzi

Briand

et al. 2009

Journal of General Virology

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“…The CGI includes core promoter elements like a regulatory heat shock element (HSE), a consensus BRE motif, which is followed by a canonical TATA box (first described by Marcos-Carcavilla et al (2008)) and an Inr consensus motif which includes one TSS (A +1 ). They are located precisely at positions −89, −39, and −30 relative to TSS, respectively.…”

Section: Hsp90aa1 Promoter Structure and Associated Cpg Islandmentioning

confidence: 99%

“…Hsp90α is necessary for spermatogenesis and meiotic progression in mammalian testis (Grad et al 2010). The ovine HSP90AA1 gene has been studied thoroughly by our group since 2008 (Marcos-Carcavilla et al 2008, 2010aOner et al 2012;Salces-Ortiz et al 2013, 2015a. A recent functional analysis of the ovine HSP90AA1 gene (Salces-Ortiz et al 2015c) has demonstrated that two linked polymorphisms, a cytosine insertion (g.667_668insC; rs397514115) and a C to G transversion (g.660G>C; rs397514116), both located at the promoter region, are mainly responsible for the observed differences in the expression rate of the gene in response to heat stress events.…”

Section: Introductionmentioning

confidence: 99%

In silico analysis of regulatory and structural motifs of the ovine HSP90AA1 gene

Gonzalez¹,

Salces-Ortiz²,

Calvo

et al. 2016

Cell Stress and Chaperones

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Gene promoters are essential regions of DNA where the transcriptional molecular machinery to produce RNA molecules is recruited. In this process, DNA epigenetic modifications can acquire a fundamental role in the regulation of gene expression. Recently, in a previous work of our group, functional features and DNA methylation involved in the ovine HSP90AA1 gene expression regulation have been observed. In this work, we report a combination of methylation analysis by bisulfite sequencing in several tissues and at different developmental stages together with in silico bioinformatic analysis of putative regulating factors in order to identify regulative mechanisms both at the promoter and gene body. Our results show a "hybrid structure" (TATA box + CpG island) of the ovine HSP90AA1 gene promoter both in somatic and nondifferentiated germ tissues, revealing the ability of the HSP90AA1 gene to be regulated both in an inducible and constitutive fashion. In addition, in silico analysis showed that several putative alternative spliced regulatory motifs, exonic splicing enhancers (ESEs), and G-quadruplex secondary structures were somehow related to the DNA methylation pattern found. The results obtained here could help explain the differences in cell-type transcripts, tissue expression rate, and transcription silencing mechanisms found in this gene.

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“…Within this region, previous results indicate that the HSP90AA1 gene, which encodes the inducible form of the cytoplasmic Hsp90α chaperone, is a good functional and positional candidate gene acting as a modulator of the response to SC in sheep (Marcos-Carcavilla et al 2008).…”

Section: Introductionmentioning

confidence: 98%

“…We previously hypothesized that after SC infection, PrP Sc starts to accumulate because its degradation is impaired (Marcos-Carcavilla et al 2008). Therefore, Hsp90 could contribute to the correct folding of PrP Sc instead of participating in other functions as the repression of heat shock factor 1 (HSF1) or the maintenance of the 26S proteasome and, thus, result in an increased expression of other heat shock proteins and in a minor proteasomal function.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the HSP90AA1 5′ flanking region are associated with scrapie incubation period in sheep

Marcos-Carcavilla¹,

Moréno²,

Serrano³

et al. 2010

Cell Stress and Chaperones

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Susceptibility to scrapie is mainly controlled by point mutations at the PRNP locus. However, additional quantitative trait loci (QTL) have been identified across the genome including a region in OAR18. The gene which encodes the inducible form of the cytoplasmic Hsp90 chaperone (HSP90AA1) maps within this region and seems to be associated with the resistance/susceptibility to scrapie in sheep. Here, we have analyzed several polymorphisms which were previously described in the ovine HSP90AA1 5′ flanking region and in intron 10 in two naturally scrapie infected Romanov sheep populations. First, we have studied 58 ARQ/VRQ animals pertaining to the sire family where the QTL influencing scrapie incubation period in OAR18 was detected. We have found a significant association between polymorphisms localized at −660 and −528 in the HSP90AA1 5′ flanking region and the scrapie incubation period. These two polymorphisms have also been studied in a second sample constituted by 62 VRQ/ VRQ sheep showing an extreme incubation period. Results are concordant with the first dataset. Finally, we have studied the HSP90AA1 expression in scrapie and control animals (N=41) with different HSP90AA1 genotypes by real time PCR on blood samples. The HSP90AA1 expression rate was equivalent in CC −600 AA −528 and CG −600 AG −528 scrapie resistant animals (ARR/ARR) and was higher in their CC −600 AA −528 than in their CG −600 AG −528 scrapie susceptible counterparts (VRQ/VRQ). Our results support the hypothesis that the ovine HSP90AA1 gene acts as a modulator of scrapie susceptibility, contributing to the observed differences in the incubation period of scrapie infected animals with the same PRNP genotype.

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Structural and functional analysis of the HSP90AA1 gene: distribution of polymorphisms among sheep with different responses to scrapie

Cited by 18 publications

References 43 publications

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

In silico analysis of regulatory and structural motifs of the ovine HSP90AA1 gene

Polymorphisms in the HSP90AA1 5′ flanking region are associated with scrapie incubation period in sheep

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