MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
Hum Mutat. 2010 Jul;31(7):E1551-63. doi: 10.1002/humu.21281.
Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non- or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease.
人类朊病毒蛋白基因（PRNP）开放阅读框（ORF）的突变几乎可以解释所有报道的家族性朊病毒病。全球更为常见的突变：八肽重复插入、P102L、D178N、E200K 和 V210I 已在大型多代家族中发生，并表现出常染色体显性遗传，但也有许多报道的罕见遗传变化其致病性不确定。基于伦敦 MRC 朊病毒单位 19 年的 PRNP 测序以及对来自怀疑患有朊病毒病的患者和健康人群的 3664 个样本的分析，我们提出了新的等位基因组合、健康对照人群数据、对整个转诊系列 DNA 中 PRNP ORF 进行筛查的结果以及 CEPH 人类基因组多样性细胞系面板。在详细介绍病例史的 10 个患者检测到的等位基因中，有 4 个未报告（G54S、D167N、V209M、Q212PP），两个变化被认为是致病性的，但在我们的地区没有描述（来自英国的 P105L、来自印度和土耳其的 G114V），其余的在健康对照人群或与已知致病性突变呈反式存在，提示非致病性或低致病性（G54S、1-OPRI、G142S、N171S、V209M、E219K）。新的基因型-表型相关性和群体频率将有助于诊断和遗传咨询那些疑似遗传性朊病毒病的患者。
