National CJD Surveillance Unit, University of Edinburgh, Bryan Matthews Building, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
BMC Med Genet. 2009 Dec 26;10:146. doi: 10.1186/1471-2350-10-146.
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.
DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation.
147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had PRNP codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full PRNP gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism.
This analysis of PRNP genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.
对疑似克雅氏病（CJD）患者的人类朊病毒蛋白基因（PRNP）进行基因分析，对于准确诊断和病例分类是必要的。先前关于 PRNP 基因座遗传变异的出版物强调，除了众所周知的 129 密码子外，还存在许多多态性，在地理位置不同的人群中存在显著的变异性。因此，考虑它们对易感性或临床病理疾病表型的影响是很有意义的。本研究旨在对英国人群来源的疾病和对照样本中除 129 密码子以外的 PRNP 开放阅读框多态性的频率和影响进行特征描述。
从血液样本中提取 DNA，并通过对朊病毒蛋白基因进行全长序列分析或使用针对研究中基因多态性的特定限制酶进行限制片段长度多态性分析，获得遗传数据。
英国的 166 例变异型克雅氏病（vCJD）确诊病例中有 147 例进行了 PRNP 129 密码子基因分型，所有病例在 129 密码子均为蛋氨酸纯合子；118 例进行了完整的 PRNP 基因测序。在后者中，有 5 例显示出其他多态性位点：219 密码子（2 例，1.69%），202 密码子（2 例，1.69%），以及八肽重复区的 24 个碱基缺失（1 例，0.85%）。E219K 和 D202D 未在散发性克雅氏病（sCJD）病例中发现，因此可能是 vCJD 的遗传风险因素。对 309 例英国确诊 sCJD 患者的基因分析显示，129 密码子基因型频率为 MM：59.5%（n=184），MV：21.4%（n=66），VV：19.1%（n=59）。有 13 例（4.2%）存在 A117A 多态性，其中 1 例还存在 P68P 多态性，4 例（1.3%）存在 24 个碱基缺失，1 例患者在 167 密码子处出现新的错义变异。由于该病例的表型与 sCJD 相似，且无家族性 CJD 病史，因此尚不清楚这是否是一种遗传 CJD 形式，还是仅仅是一种中性多态性。
本研究对英国 CJD 患者的 PRNP 遗传变异进行了分析，首次与来自同一人群的 970 名健康个体（n=970）进行了全面比较，这些健康个体对三种最常见的变异（129 密码子、117 密码子和 24 个碱基缺失）进行了基因分型。在英国 sCJD 或 vCJD 病例和正常（健康献血者）英国人群中，后两种遗传变异的频率相等。
