MOLECULAR GENETICS OF FAMILIAL TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

家庭传染性疾病的流行率 海绵状脑病（TSE），特别是 Creutzfeldt-Jakob病类型未知。分子遗传 对患者及其家属的研究是有意义的，以便（1） 确定PRNP中点突变的分布和类型 （2）发现新的突变， 这些疾病;（3）确定各种疾病之间的联系 突变类型与疾病表型和临床表现。 在本报告所述期间，我们进行了 在全球范围内进行合作研究，并收到了超过 500个血液样本，供分析，样本来自携带 CJD、GSS和/或FFI的推定诊断。开展 在这些研究中，我们扩大了我们的程序，以寻找其他作为 然而，除了那些最常见的突变之外， 在密码子178、200和210处检测到。这种扩展的方法 导致识别三个新的突变，一个在密码子 150处，一个在密码子180处，一个在密码子187处。密码子150 此前只有两名日本人报告了这种突变 家庭，这是第一次报告，它发生在美国 一个非亚裔家庭中没有已知家庭的国家 在我们的发现之前。我们发现了一个大的 一个在密码子102处发生突变的美国-意大利家族， 已经有八个GSS病例。一个活着的家庭成员 诊断为携带密码子102突变（脯氨酸<亮氨酸） 27岁时被诊断为早发性阿尔茨海默病患者 目前37岁，完全痴呆，在养老院 是三个孩子的母亲这个家族的家谱 表明这种病是100%可传染的西方免疫印迹法 提取的PrPres揭示了一个独特的带型， 作为GSS的分子标记带型显示 在8和14 kDa的PrP的不同的非糖基化片段。 光密度分析显示， 三种主要的糖型与 散发性或医源性CJD。

The prevalence of familial forms of transmissible spongiform encephalopathies (TSEs) particularly of the Creutzfeldt-Jakob disease type is unknown. Molecular genetic studies of patients and their families is of interest in order to (1) determine the distribution and types of point mutations in the PRNP gene worldwide; (2) to discover new mutations associated with these diseases; and, (3) to determine the association of the various types of mutations with disease phenotypes and clinical expression. During the period covered by this report we conducted collaborative studies on a worldwide basis and received more than 500 blood specimens for analysis from patients carrying a presumptive diagnosis of CJD, GSS, and/or FFI. In conducting these studies we broadened our procedures to search for other as yet unidentified mutations in addition to those most frequently detected at codons 178, 200, and 210. This expanded approach has resulted in the recognition of three new mutations, one at codon 150, one at codon 180 and one at codon 187. The codon 150 mutation had previously been reported in only two Japanese families and this is the first report of its occurrence in the United States in a non-Asian family in which there was no known family histoy prior to our findings. We have identified a large American-Italian family with a mutation at codon 102 in which there have been eight cases of GSS. One living family member carrying the codon 102 mutation (Proline<Leucine) was diagnosed clinically at age 27 as early onset Alzheimer's disease. The patient is currently 37 years of age, is fully demented, is in a nursing home and is the mother of three children. The geneology of this family shows that the diease is 100% penetrable. Western imunoblotting of extracted PrPres revealed a unique banding profile that may serve as a molecular marker for GSS. The banding pattern showed distinct unglycosylated fragments of PrP at 8 and 14 kDa. Densitometric analysis revealed that the relative proportions of the three major glycoforms were significantly different than those of sporadic or iatrogenic forms of CJD.