MOLECULAR GENETICS OF FAMILIAL TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

家族性传播疾病的流行情况 海绵状脑病(TSE) 克雅病类型未知。分子遗传学 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 全球范围内的基因；(2)发现与 这些疾病；以及，(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份血液样本用于分析携带A型肝炎病毒的患者 推定诊断为CJD、GSS和/或FFI。在指挥中 这些研究拓宽了我们的研究程序，以寻找其他AS 然而，除了那些最常见的 在密码子178、200和210处检测到。这种扩展的方法具有 导致识别出三个新的突变，一个在密码子上 150，一个在密码子180，一个在密码子187。密码子150 此前只有两名日本人报告过突变 家庭，这是在美国发生的第一次报告 一个非亚洲家庭中的国家，其中没有已知的家庭 在我们发现之前的历史记录。我们发现了一个大型的 有密码子102突变的美籍意大利家庭 目前已有8例GSS病例。一名在世的家庭成员 诊断为携带密码子102突变(Pro和lt；亮氨酸) 临床上27岁时被诊断为早发性阿尔茨海默病。病人是 目前37岁，完全精神错乱，住在养老院 她是三个孩子的母亲。这个家族的遗传学 表明这种疾病是100%可穿透的。西方的印迹 提取的PrPres揭示了一个独特的带型特征，可能 作为GSS的分子标记。条带图案显示 PrP在8 kDa和14 kDa处有明显的非糖基化片段。 密度学分析表明， 三种主要糖型与红曲霉的糖型有显著差异 散发性或医源性的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.