Lack of association between PRNP 1368 polymorphism and Alzheimer's disease or vascular dementia

Background  

Polymorphisms of the prion protein gene (PRNP) at codons 129 and 219 play an important role in the susceptibility to Creutzfeldt-Jakob disease (CJD), and might be associated with other neurodegenerative disorders. Several recent reports indicate that polymorphisms outside the coding region of PRNP modulate the expression of prion protein and are associated with sporadic CJD, although other studies failed to show an association. These reports involved the polymorphism PRNP 1368 which is located upstream from PRNP exon 1. In a case-controlled protocol, we assessed the possible association between the PRNP 1368 polymorphism and either Alzheimer's disease (AD) or vascular dementia (VaD).     

PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism

Background  

Genetic analysis of the human prion protein gene (PRNP) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the PRNP locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of PRNP open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population.     

Genetic Studies in Human Prion Diseases

Human prion diseases are fatal neurodegenerative disorders that are characterized by spongiform changes, astrogliosis, and the accumulation of an abnormal prion protein (PrP^Sc). Approximately 10%-15% of human prion diseases are familial variants that are caused by pathogenic mutations in the prion protein gene (PRNP). Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. These mutations vary significantly in frequency between countries. Here, we compare the frequency of PRNP mutations between European countries and East Asians. Associations between single nucleotide polymorphisms (SNPs) of several candidate genes including PRNP and CJD have been reported. The SNP of PRNP at codon 129 has been shown to be associated with sporadic, iatrogenic, and variant CJD. The SNPs of several genes other than PRNP have been showed contradictory results. Case-control studies and genome-wide association studies have also been performed to identify candidate genes correlated with variant and/or sporadic CJD. This review provides a general overview of the genetic mutations and polymorphisms that have been analyzed in association with human prion diseases to date.

Graphical Abstract

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Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study

Background

A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt‐Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion‐like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND.

Methods

We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI‐TOF mass spectrometry.

Results

In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over‐represented or under‐represented in our cohort of patients with sCJD.

Conclusion

Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.     

Mutation of the PRNP gene at codon 211 in familial Creutzfeldt‐Jakob disease

Creutzfeldt‐Jakob disease (CJD) belongs to a group of chronic, progressive, neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary CJDs are associated with mutations in the PRNP gene on chromosome 20p12‐pter. We report a family in which four patients developed classical clinical signs of CJD, including severe cognitive decline, cerebellar signs, myoclonic jerks, and synchronic periodic discharges on electroencephalogram. The E211Q mutation has been identified in family members, but not in 97 sporadic CJD patients referred to the Italian registry of CJD nor in 205 healthy normal subjects, suggesting a pathogenic role for this mutation. © 2001 Wiley‐Liss, Inc.     

No evidence for prion protein gene locus multiplication in Creutzfeldt-Jakob disease

Precedent of causative multiplication of key gene loci exists in familial forms of both Alzheimer's and Parkinson's diseases. Genetic Creutzfeldt-Jakob disease (CJD) is often clinically indistinguishable from sporadic disease and inexplicably, a negative family history of a similar disorder occurs in around 50–90% of patients harboring the most common, disease-associated, prion protein gene (PRNP) mutations. We undertook semi-quantitative analysis of the PRNP copy number in 112 CJD patients using quantitative polymerase chain reaction. All included cases satisfied classification criteria for probable or definite sporadic CJD, ascertained as part of longstanding, prospective, national surveillance activities. No examples of additional copies of the PRNP locus as an explanation for their disease was found in any of the 112 sporadic CJD patients. Hence, contrasting with more common, age-related neurodegenerative diseases, the genetic aetiology in human prion disease continues to appear entirely restricted to small scale mutations within a single gene, with no evidence of multiplication of this validated candidate gene locus as a cause.     

Metabolic profiling reveals therapeutic effects of <Emphasis Type="Italic">Herba Cistanches</Emphasis> in an animal model of hydrocortisone-induced 'kidney-deficiency syndrome'

Background  

Herba Cistanches (Roucongrong) is effective in treating Shenxu Zheng ('kidney-deficiency syndrome'). However, the mechanisms and systemic metabolic responses to the herbal intervention are unclear.     

<Emphasis Type="Italic">In vivo</Emphasis> activity of <Emphasis Type="Italic">Sapindus saponaria</Emphasis> against azole-susceptible and -resistant human vaginal <Emphasis Type="Italic">Candida</Emphasis> species

Background  

Study of in vivo antifungal activity of the hydroalcoholic extract (HE) and n-BuOH extract (BUTE) of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida spp.     

Antiviral biflavonoids from <Emphasis Type="Italic">Radix Wikstroemiae</Emphasis> (<Emphasis Type="Italic">Liaogewanggen</Emphasis>)

Background  

Radix Wikstroemiae is a common Chinese herbal medicine. The ethyl acetate fraction of the ethanolic extract of W. indica possesses potent in vitro antiviral activity against respiratory syncytial virus (RSV). This study aims to identify the antiviral components of the active fraction.     

Functional polymorphisms in <Emphasis Type="Italic">XRCC</Emphasis>-<Emphasis Type="Italic">1</Emphasis> and <Emphasis Type="Italic">APE</Emphasis>-<Emphasis Type="Italic">1</Emphasis> contribute to increased apoptosis and risk of ulcerative colitis

Objective  

The present study was designed to investigate the role of X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1 (APE1) polymorphisms in apoptosis and the risk of ulcerative colitis (UC).     

Additive effects of <Emphasis Type="Italic">LPL</Emphasis>, <Emphasis Type="Italic">APOA5</Emphasis> and <Emphasis Type="Italic">APOE</Emphasis>variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

Background  

Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.     

Associations between <Emphasis Type="Italic">interleukin</Emphasis>-<Emphasis Type="Italic">23R</Emphasis> polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis

Objective  

The aim of this study was to determine whether interleukin-23R (IL-23R) polymorphisms confer susceptibility to ankylosing spondylitis (AS).     

DNA methylation and mRNA expression of <Emphasis Type="Italic">SYN III</Emphasis>, a candidate gene for schizophrenia

Background  

The synapsin III (SYN III) gene on chromosome 22q is a candidate gene for schizophrenia susceptibility due to its chromosome location, neurological function, expression patterns and functional polymorphisms.     

Tian Xian Liquid (TXL) induces apoptosis in HT-29 colon cancer cell <Emphasis Type="Italic">in vitro</Emphasis> and inhibits tumor growth <Emphasis Type="Italic">in vivo</Emphasis>

Background  

Tian Xian Liquid (TXL) is a Chinese medicine decoction and has been used as an anticancer dietary supplement. The present study aims to investigate the effects of TXL on the apoptosis of HT-29 cells and tumor growth in vivo.     

Anticonvulsant effects of aerial parts of <Emphasis Type="Italic">Passiflora incarnata</Emphasis> extract in mice: involvement of benzodiazepine and opioid receptors

Background  

Passion flower (Passiflora incarnata) is used in traditional medicine of Europe and South America to treat anxiety, insomnia and seizure. Recently, it has shown antianxiety and sedative effects in human.     

Sporadic Creutzfeldt–Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties

The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt–Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these “pure” cases, “mixed” cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co‐occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft‐associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.     

Effects of <Emphasis Type="Italic">MCF2L2, ADIPOQ</Emphasis> and <Emphasis Type="Italic"> SOX2</Emphasis> genetic polymorphisms on the development of nephropathy in type 1 Diabetes Mellitus

Background  

MCF2L2, ADIPOQ and SOX2 genes are located in chromosome 3q26-27, which is linked to diabetic nephropathy (DN). ADIPOQ and SOX2 genetic polymorphisms are found to be associated with DN. In the present study, we first investigated the association between MCF2L2 and DN, and then evaluated effects of these three genes on the development of DN.     

Anti-oxidative effects of the biennial flower of <Emphasis Type="Italic">Panax notoginseng</Emphasis> against H<Subscript>2</Subscript>O<Subscript>2</Subscript>-induced cytotoxicity in cultured PC12 cells

Background  

Radix notoginseng is used in Chinese medicine to improve blood circulation and clotting; however, the pharmacological activities of other parts of Panax notoginseng have yet to be explored. The present study reports the anti-oxidative effects of various parts of Panax notoginseng.     

Analysis of sequence variations in the suppressor of cytokine signaling (<Emphasis Type="Italic">SOCS</Emphasis>)<Emphasis Type="Italic">-3</Emphasis>gene in extremely obese children and adolescents

Background  

The suppressor of cytokine signaling (SOCS)-3 is a negative feedback regulator of cytokine signaling and also influences leptin signaling. We investigated association of variations in the coding sequence and promoter region of SOCS3 with extreme obesity in German children and adolescents.