Prion病的朊蛋白基因研究进展

Prion病是指一组可传递的海绵状脑病 ( transm issiblespongiform encephalopathy,TSE)。大量研究表明该病是一种称为朊蛋白 ( prion protein,Pr P)的异构体 ( protease- resis-tant prion protein,Pr P- res)在脑内沉积所致 [1 ] 。正常的朊蛋白的非致病性异构体 ( norm al cellular isform of the prion pro-tein,Pr P- c)是由位于第 2 0对染色体短臂上的朊蛋白基因( prion protein gene,PRNP)编码 ,它由 2 5 3个氨基酸组成 [2 ] 。 Pr P- res与 Pr P- c的主要区别在于它含有较多的β片层结构和抗蛋白酶消化的特征 [3 ]。目前 ,普…     

朊蛋白病误诊为抑郁症1例

1病例患者女,54岁。2011年2月因退休后出现情绪低落、懒惰、易激惹、记忆减退,在当地医院诊断为抑郁症给予抗抑郁治疗。第3天因患者突然出现大喊大叫、发脾气、摔东西、说话不着边际而住当地医院。入院3d,患者不语不动、说话难以听懂、尿失禁。1周后出现肌痉挛并昏迷。     

典型Creutzfeldt-Jakob病一例

<正>1病例报告患者女性,52岁,农民,主因认知功能进行性下降伴肢体抽动8个月,加重2个月入院。患者8个月前无明显诱因出现认知功能下降,表现为记忆力减退,不能记起近期事件,夜间间断出现右侧肢体抽动及睁眼,伴失眠及烦躁,无言语障碍,生活可自理,未予诊治。6个月前患者出现反应迟钝,做日常家务能力明显下降,间断出现言语困难,表现为不能完整叙述整句话,逐渐出现重复性语言及行为,就诊于当地医院,考虑为抑郁症,给予口服药物(具     

朊蛋白病

人类朊蛋白病(PrDs)是一类既表现为神经退行性病变又具有感染性的少见疾病,虽然发病率较低,但是近年来由于对疯牛病及其它可感染人类的动物源性PrDs危险性的高度重视,人类PrDs受到了广泛的关注。本文综述了PrDs临床和病理的主要表现及目前的诊断方法,同时提及一些帮助人们认识这类疾病相关的发病机制和朊蛋白(PrP)可感染性的重要特征。     

精神分裂症合并克-雅氏病1例

患者男,41岁。既往史无特殊。性格孤僻,内向。家族史阴性。患者18岁时患精神分裂症在我院住院治疗,服用奋乃静,4个月后进步出院。出院后未坚持服药,病情渐重,生活不能自理,外走。22年后第2次住院。入院时精神状态：意识清晰,幻听,思维贫乏,情感淡漠,明显衰退。给予奋乃静治疗,最大剂量22mg／d。因出现锥体外系反应换用舒必利后无药物不良反应。1年余后患肠炎,1周痊愈。此后出现步态不稳,反应迟钝,口齿不清,肌张力高。停用舒必利加用苯海索无效。     

朊蛋白病的研究进展

朊蛋白病是人类及动物罕见的致命性中枢神经系统变性病，现在认为由朊蛋白（Prion）这一非寻常病原体引起。临床表现为进行性痴呆、共济失调、肌阵挛，可伴有锥体系及锥体外系症状，多在数月至一年内死亡。其脑组织病理学呈现神经元空泡变性，即海绵样变性，胶质细胞增生肥大、     

Creutzfeldt-Jakob病非侵入性诊断方法研究新进展

朊病毒是一种非常规意义上的传染性病原体,常导致致命性神经系统疾病,其中以Creutzfeldt-Jakob病(CJD)最为常见。CJD属于一种罕见的神经系统退行性疾病,临床进展迅速,致死性达100%。此疾病有多种类型,其中以散发型最为常见。目前此病的最大挑战即临床诊断。到目前为止临床确诊的金标准仍为脑组织活检,但将其作为诊断金标准仍存在一定局限性。随着研究的逐步进展,亟需探讨新的非侵入性的检测(手段),以利于疾病诊断。本文就有关CJD生物标记物检测、基因筛查、影像学检查及电生理检查等非侵入性手段的研究进展进行综述,旨在协助CJD的诊断,为CJD的确诊提供新的思路。     

朊蛋白病百年历史回顾

人们首次认识并报道朊蛋白病可追溯至1922年克雅氏病的提出。一百年来, 从对临床症状的困惑到典型组织病理学改变的描述, 从提出"朊蛋白假说"到发现朊蛋白病相关基因, 人们对朊蛋白病的认识在不断加深, 朊蛋白病也逐渐成为一组少见的传染性致死性退行性脑病的总称, 主要包括克雅氏病及其变异型、Kuru病、Gerstmann-Straussler-Scheinker综合征、家族性致死性失眠等。本文现从克雅氏病的发现入手, 详述朊蛋白病特征性病理改变的发现、传染性的验证、朊蛋白及PRNP基因的发现, 以及朊蛋白病多种亚型的临床表现、病理改变、基因突变类型等, 拟通过回顾朊蛋白病的研究历史, 帮助临床同道更深入地了解该病诊断治疗的进展及困境。     

家族性Creutzfeldt-Jakob病

目的确定家族性Creutzfeldt—Jakob病（CJD）的临床特点并探讨其可能的发病机制。方法对一个CJD家系进行系谱调查,并采用蛋白捕获法进行脑脊液14-3—3蛋白定量;应用PCR方法,结合DNA测序技术,检测朊蛋白（PrP）基因类型。结果（1）两代4例的发病年龄早于散发性CJD,而且有早发的趋势;（2）先证者脑脊液14-3—3蛋白为125ng／ml,高出截点13．9。倍;（3）先证者PRNP第788碱基和789碱基之间插入1个碱基A,致使PRNP第231位点发生插入突变;（4）患者弟弟及其女儿未发现有PrP基因突变。结论先证者为PRNP第231位点插入突变致家族性CJD,其临床表型与散发性CJD无明显不同,但发病年龄早于散发性CJD,同一家系患者死于同一年龄段。     

Creutzfeldt-Jakob病患者尿蛋白酶抵抗性朊蛋白同工型的检测

目的观察Creutzfeldt—Jakob病(CJD)患者的尿蛋白酶抵抗性朊蛋白(PrP^SC)同工型,研究CJD新的诊断途径。方法采用抗朊蛋白(PrP)单克隆抗体3174进行免疫印迹法检测5例CJD患者和20例其他神经系统疾病患者的尿样。结果1例CJD患者尿中PrP^SC同工型免疫反应阳性,其余CJD患者及其他神经系统疾病患者尿样检测均阴性。结论检测尿中PrP^SC同工型为CJD的诊断提供了新的途径。     

Creutzfeldt-Jakob disease associated with a deletion of two repeats in the prion protein gene

A two-octapeptide repeat deletion of the prion protein gene has been recently observed in a patient with a 2-year history of dementia and a clinical diagnosis of possible Creutzfeldt-Jakob disease (CJD). The authors report a similar deletion in a patient with a definitive diagnosis of CJD. Since the two-repeat deletion has not been observed in large, population-based studies, the two cases suggest that this deletion is a new pathogenic mutation associated with CJD.     

Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease

BACKGROUND: The transmissible spongiform encephalopathies constitute a fascinating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of iatrogenically transmitted cases, approximately 85% to 90% of patients develop CJD without identifiable explanation, with an increasing number of different mutations in the prion protein gene (PRNP) recognized as probably causative in the remainder. OBJECTIVE: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. METHODS: Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient, including magnetic resonance imaging of the brain, electroencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta protein. Standard postmortem neuropathological examination of the brain was performed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. RESULTS: Concomitant with the exclusion of alternative diagnoses, the presence of characteristic periodic sharp-wave complexes on the electroencephalogram in combination with a positive result for 14-3-3 beta protein in the cerebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mutation consisting of an adenine-to-guanine substitution at nucleotide 611, causing alanine to replace threonine at codon 188. CONCLUSIONS: In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.     

Creutzfeldt-Jakob disease in a patient with an R208H mutation of the prion protein gene (PRNP) and a 17-kDa prion protein fragment

A case of Creutzfeldt-Jakob disease (CJD) with a rare mutation of the prion protein (PrP) gene (PRNP) at codon 208 (R208H) is described. By comparison with two preceding reports, the case described here displayed two distinct biochemical and neuropathological features. Western blot analysis of brain homogenates showed, in addition to the commonly observed three bands of abnormal protease-resistant PrP isoform (PrP^Sc), an additional band of about 17 kDa. Neuropathological examination of the post mortem brain revealed tau pathology in the hippocampus and entorhinal cortex, as well as ballooned neurons in the cortex, hippocampus and subcortical gray matter.     

Familial Creutzfeldt-Jakob disease with a novel 120-bp insertion in the prion protein gene

The clinical course, neuropathological features, and genetic findings in 3 members of a German family carrying a novel 120-bp insertion in the prion protein (PrP) gene are described. Genetic analysis of the mutated allele revealed a sequence of five extra octapeptide repeats, distinct from those of the two previously reported families with an insertion of this size. There was distinctive variation in the clinical course and the onset and duration of the illness in the documented subjects. Neuopathological evaluation showed neuronal loss and gliosis in the neocortex of the 3 examined cases; spongiform degeneration was found in 2 of them. PrP immunoreactivity of unusual morphology and distinct distribution was present in the cerebellem and neocortex ("blurred staining") of 2 examined cases. One subject showed features usually found in sporadic Creutzfeldt-Jacob disease with a punctate type of PrP deposition in the cerebellum. In addition, there were some plaque-like PrP aggregates morophologically similar to the other 2 cases in the molecular layer of the cerebellum, and unusual Prp immunoreactivity ("fleecy staining") was found in the neocortex. The clinicopathological heterogeneity in the documented family is in accordance with the phenotypic variability associated with previously reported insertions.     

散发性Creutzfeldt-Jakob病患者10例prion基因研究

目的 检测10例Creutzfeldt-Jakob病（CJD）患者prion基因（PRNP）外显子突变情况.方法 抽取患者外周静脉血,提取DNA,PCR法扩增PRNP外显子后直接测序,并用限制性内切酶Nsp Ⅰ检测PRNP 129位点密码子基因型.结果 2例肯定CJD患者中,1例PRNP检测未见异常,另1例PRNP第729碱基G被C取代（729G→C）,使编码prion第211个氨基酸的密码子GAG变成了GAC,翻译后第211个氨基酸由谷氨酸变为天冬氨酸（E211D）.8例很可能CJD患者中,2例PRNP第751碱基G被A取代（751G→A）,使编码prion第219个氨基酸的密码子GAG变成了AAG,翻译后第219个氨基酸由谷氨酸变为赖氨酸（E219K）.10例CJD患者PRNP 129位点密码子基因型都是甲硫氨酸纯合型.结论 1例肯定CJD患者的prion基因外显子存在一种新的点突变E211D,这很可能是导致遗传prion病发生的原因.2例很可能CJD患者的prion基因突变E219K,与M129V同属于基因多态性,而不是致病原因.prion基因检测有助于prion病的诊断.     

Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion

We describe a patient who was clinically diagnosed with familial early-onset Alzheimer disease (AD) carrying both the E318G substitution in presenilin 1 (PSEN1) and an insertion of 7 octapeptide coding repeats in the prion protein gene (PRNP). Neuropathological examination revealed elongated cerebellar prion protein deposits in the absence of AD pathology. Further analysis of other family members showed that the Creutzfeldt-Jakob disease phenotype in this family was caused solely by the PRNP insertion. This observation is consistent with our previous finding that PSEN1 E318G is not causally related to AD. Received: 14 July 1999, Received in revised form: 15 September 1999, Accepted: 12 January 2000     

Pathologic prion protein spreading in the peripheral nervous system of a patient with sporadic Creutzfeldt-Jakob disease

BACKGROUND: Involvement of the peripheral nervous system in the pathogenesis of prion diseases is becoming increasingly evident. However, pathologic protease-resistant prion protein deposition in the peripheral nerves of patients with Creutzfeldt-Jakob disease has never been demonstrated, to our knowledge. OBJECTIVE: To determine whether mutated prion protein accumulation could be shown in the peripheral nervous system of patients with sporadic Creutzfeldt-Jakob disease. DESIGN: Autopsy study. PATIENTS: Three patients with sporadic Creutzfeldt-Jakob disease. INTERVENTIONS: Study of the brain, spinal cord, and sciatic and superficial peroneal nerves by immunohistochemistry and Western blot analysis. MAIN OUTCOME MEASURE: Demonstration of protease-resistant prion protein accumulation. RESULTS: In all cases, protease-resistant prion protein accumulation was found in the brain and posterior horns of the spinal cord. In 1 case, protease-resistant prion protein deposits were also evidenced in the dorsal root ganglia and the superficial peroneal nerve. CONCLUSIONS: Protease-resistant prion protein may be found in the peripheral nervous system of some patients with sporadic Creutzfeldt-Jakob disease. However, a larger series is required to assess the incidence of peripheral nervous system involvement and to discuss the diagnostic usefulness of peripheral nerve biopsy in sporadic Creutzfeldt-Jakob disease.     

A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease

Complete sequencing of the prion protein open reading frame of a 68-year-old woman affected by a familial form of Creutzfeldt-Jakob disease (CJD) revealed a new mutation at codon 210 resulting in the substitution of isoleucine for valine. Moreover, a new 24-bp deletion encompassing codons 54 to 61 or 62 to 69 was found in the other allele. Four of the 17 asymptomatic relatives tested carry the 210 mutation. Two of them were 81 and 82 years old. Four of 22 patients with CJD whose recorded familial history was negative for demented illnesses, but none of 103 healthy control subjects, tested positive for the 210 mutation. These data suggest that the 210 mutation is associated with CJD, but that environmental factors or incomplete penetrance may contribute to the development of the disease. This finding also suggests that in Italy, familial CJD is more common than previously reported.     

An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease

In a pedigree with Creutzfeldt-Jakob disease we identified a 144-bp insertion in the open reading frame of the prion protein (PrP) gene. The insertion is in-frame and codes for 6 extra uninterrupted octapeptide repeats in addition to the 5 that are normally present in the N-terminal region of the protein. The possibility that this mutation may prove relevant to elucidating the mechanism of horizontal transmission of the spongiform encephalopathies is discussed.     

Creutzfeldt-Jakob disease associated with the R208H mutation in the prion protein gene

The authors investigated a patient who died of apparent sporadic Creutzfeldt-Jakob disease (CJD) but carried a R208H substitution in the prion protein (PrP). The patient phenotype was indistinguishable from typical sporadic CJD (i.e., MM1 subtype). In addition, pathologic PrP, PrP(Sc), originated from both the normal and the mutated PRNP allele and had the same characteristics as PrP(Sc) type 1. The authors propose that the R208H mutation influences disease susceptibility without significantly affecting PrP(Sc) properties or disease phenotype.