朊蛋白基因多态性与老年性痴呆的相关性研究

目的探讨朊蛋白基因(PRNP)129密码子多态性与老年性痴呆(AD)发病的相关性。方法采用病例-对照研究方法,以PCR-RFLP方法检测驻京部队干休所60例晚发AD(LOAD)患者与92例健康老年对照的PRNP129密码子基因、ApoEε4等位基因多态性。结果驻京部队干休所汉族老年人群中PRNP129密码子甲硫氨酸纯合(MM)基因型频率为94.08%,甲硫氨酸缬氨酸杂合(MV)基因型频率为5.92%,未发现缬氨酸纯合(VV)型。ApoEε4等位基因分层前后,MM基因型发生LOAD的风险性差异无统计学意义。PRNP129密码子MM型不是LOAD的独立危险因素(OR=3.27,95%CI=0.402～26.605)。结论东亚人群与欧洲人群PRNP129密码子多态性分布不同。PRNP129密码子MM基因型携带者发生LOAD的风险无显著增高,提示MM基因型不参与LOAD发病。     

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.     

抑郁症患者的APOE基因多态性及血脂水平的研究

目的探索载脂蛋白E(apolipoprotein E,APOE)基因多态性与抑郁症之间的关系及其对抑郁症患者脂代谢的影响。方法对92例符合中国精神障碍分类与诊断第三版(CCMD-3)抑郁发作的患者和60例正常对照进行APOE基因分型、测量他们的体重、身高、腰围、臀围,并测定血脂水平,包括总胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)。以17项汉密尔顿抑郁量表(HAMD17)和汉密尔顿焦虑量表(HAMA)评定抑郁症患者的抑郁、焦虑症状。结果抑郁症与对照组间APOE基因型及等位基因频率无显著差异。抑郁症组中,携带APOEε4等位基因的患者平均TC显著高于不携带APOEε4等位基因的患者,差异有统计学意义(P(0.05)。对照组中,携带APOEε4等位基因者与不携带APOEε4等位基因者相比,体质参数、血脂平均值均无差异(P(0.05)。携带和不携带APOEε4等位基因的抑郁症患者TG值均分别高于携带和不携带APOEε4等位基因的对照组TG值,差异有显著性(P(0.05,P(0.01);携带和不携带APOEε4等位基因的抑郁症患者的HDL值分别比对照组相应者低,差异有显著性(P(0.01,P(0.001);携带APOEε4等位基因的抑郁症患者的HAMD17阻滞项评分高于不携带此等位基因的抑郁症患者,差异有显著性(P(0.05)。结论抑郁症与APOE基因多态性无明显关联。抑郁症患者存在一定的血脂紊乱,尤其是携带APOEε4等位基因的抑郁症患者可能有更多的血脂代谢问题,而且携带APOEε4等位基因的抑郁症患者HAMD17阻滞项评分较高。     

载脂蛋白E基因和脑血管淀粉样变在高血压脑出血中的作用

目的研究载脂蛋白E基因(APOE)与脑血管淀粉样变(CAA)在高血压脑出血(HICH)中的作用。方法随机收集HICH患者236例,其中行手术治疗的108例;采用聚合酶链反应限制性片段长度多态性法(PCRRFLP)检测所有研究对象的APOE基因型;比较两组临床特征、APOE基因型及等位基因频率分布的差异;并进一步分析手术组中发生脑血管淀粉样变与临床特征、APOE基因型及等位基因频率相关因素的关系。结果 HICH组与手术组在临床特征、等位基因及基因型分布上均无统计学差异。108例进行了手术治疗的HICH患者当中,有28例发生脑血管淀粉样改变。CAA(+)的患者发生浅部出血的比例明显高于CAA(-)的患者。CAA(+)的患者中APOEε3/4基因型及APOEε4等位基因的比例明显高于CAA(-)患者,且单因素和多因素Logistic回归分析均发现APOEε4是HICH患者发生CAA的危险因素。结论 APOEε3/4基因型和APOEε4等位基因可能是HICH发生的危险因素,也是HICH患者发生CAA的危险因素;APOE可能通过对CAA的发生和发展产生影响,进而对HIGH的发生产生作用。     

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。     

载脂蛋白E基因多态性对高血压脑出血发病的影响

目的 了解载脂蛋白E(APOE)基因多态性与高血压脑出血(HICH)发病的关系. 方 法 设计对照研究,对川北医学院附属医院神经外科自2007年9月至2010年12月收治的128例HICH患者(HICH组)及84例正常成人(对照组)采用聚合酶链反应限制性片段长度多态性法(PCR-RFLP)检测APOE基因型,比较2组对象APOE基因型及等位基因频率的差异,并进一步比较不同A POE基因型患者发病年龄、性别、血压、血脂、出血部位、血肿大小等因素的差异. 结果 HICH组有吸烟嗜好、糖尿病史的比例以及总胆固醇(TC)、低密度脂蛋白(LDL-C)浓度均明显高于对照组,差异有统计学意义(P＜0.05).HICH组APOEε3/4基因型及APOEε4等位基因的分布频率明显高于对照组,而APOEε3/3基因型、APOEε3等位基因的分布频率明显低于对照组,差异有统计学意义(P＜0.05).HICH组中APOEε3/4基因型及APOEε4等位基因携带者的发病年龄≤45岁和浅部出血的比例以及LDL-C及TC血浆浓度均明显高于APOEε3/3基因型及APOEε3等位基因携带者,发病时收缩压明显低于APOEε3/3基因型及APOEε3等位基因携带者,差异均有统计学意义(P＜0.05). 结论 APOE基因多态性对HICH的发生有重要影响,影响因素包括发病年龄、血压、血脂以及出血的部位,其机制可能与影响动脉粥样硬化和血管淀粉样变有关.     

散发性基因变异性CJD2例报告及文献回顾

目的探讨散发性基因变异性CJD的临床表现及脑电图、核磁特征,为其早期诊断与治疗提供帮助。方法对2例经外周血进行基因检测而确诊的CJD患者的临床表现、脑电图、核磁等检查进行回顾性分析,并进行相关的文献回顾。结果在病例1中我们报道了1例71岁的女性,PRNP等位基因E196K变异,129密码子是蛋氨酸纯合子基因型。该患起病无特殊的症状,但是很快出现进行性加重的言语、记忆、认知和运动障碍。在整个病程中脑电图无周期性三相波。整个病程7个月。病例2中我们报道了1例76岁的男性,PRNP等位基因E196A变异,129密码子是蛋氨酸纯合子基因型。该患以精神症状起病,很快出现言语不能、震颤、肌张力增高。脑电图记录到典型的周期性三相波,核磁表现典型,示双额顶叶、左枕叶脑表见条片状稍高信号。结论散发性基因变异性CJD起病快,临床表现多样,脑电图与核磁检查有助于诊断,结合外周血基因检测可以明确诊断。     

载脂蛋白E基因型与动脉瘤性蛛网膜下腔出血的相关性研究

目的调查中国南方地区健康人群和动脉瘤性蛛网膜下腔出血(aSAH)患者的载脂蛋白 E(APOE)基因型和频率分布特点,探讨APOE基因型与aSAH发病的关系。方法检测133例 aSAH患者和127名志愿者外周血APOE基因型,分析病例组和对照组各基因型和等位基因的频率, 计算APOE基因型与aSAH发病的相关系数。结果病例组ε4等位基因频率与对照组相比有显著性差异(P<0．05);ε2和ε3等位基因频率与对照组比较无显著性差异(P>0．05);ε4基因型携带者发生 aSAH的危险度较非ε4携带者高1．7倍(OR=1．72):ε2和ε3基因型携带者发生aSAH的危险性与对照组相比无升高(比值比分别为0．71和0．98)。结论 APOEε4基因是中国南方部分地区人群aSAH发病的危险因子。     

晚发性抑郁症患者认知功能及其与载脂蛋白E基因多态性的关联研究

目的:探讨晚发性抑郁症(LOD)患者认知功能及其与载脂蛋白E(APOE)基因多态性的关联. 方法:LOD患者97例,健康对照组44例,采用聚合酶链式反应-限制性片段长度多态性检测APOE基因多态性.所有受试者完成了汉密尔顿抑郁量表评估及神经心理学测试. 结果:患者组的神经认知测试成绩除连线测试外,其余测试成绩都显著低于正常对照组(P ＜0.001);APOE基因型和等位基因频率分布两组间差异无统计学意义.在控制年龄、教育和性别后,以APOE基因是否携带ε4等位基因将受试者分为ε4+组和ε4-组,分析APOEε4等位基因对受试者认知功能的影响,以及ε4等位基因和抑郁症的诊断交互作用对认知功能的影响.结果发现,APOEε4等位基因对LOD患者认知功能无明显的主效应,APOEε4等位基因和抑郁症的诊断之间无交互作用影响认知功能. 结论:LOD患者存在广泛的认知功能受损,APOE基因多态性与LOD的发病及认知功能未发现有显著关联.     

APOE基因多态性与抑郁症和痴呆的关联分析

目的：探索基因与抑郁症和痴呆的关联。方法：对42例单相抑郁症，39例双相抑郁症，40例痴呆和100例健康对照者进行载脂蛋白E（appolipoprotein,APOE)基因分型，计算基因频率，并对抑郁症、痴呆与APOE基因多态性进行关联分析。结果：抑郁症和痴呆的APOEε2等位基因频率比对照组低，单相抑郁症和痴呆的APOEε4等位基因频率高于对照组，且APOEε4等位基因与痴呆密切关联。结论：APOEε2基因可能是抑郁的保护因子，痴呆与单相抑郁症可能分享共同的发病因子。     

PRNP 1368 polymorphism is not associated with sporadic Creutzfeldt-Jakob disease in the Korean population

Background:  Human prion protein gene ( PRNP ) is considered a critical and fundamental gene in determining the incidence of human prion diseases. Codons 129 and 219 play an important role in the susceptibility to sporadic Creutzfeldt-Jakob disease (CJD). An association between sporadic CJD and the polymorphism ( PRNP 1368) in an upstream of PRNP exon 1 has been reported in the British and German populations, but study in the Dutch population has failed to confirm an association.
Purpose:  To investigate whether the PRNP 1368 polymorphism is associated with sporadic CJD in the Korean population.
Methods:  We compared the genotype and allele frequencies of PRNP 1368 polymorphism in 171 sporadic CJD patients with those in 212 healthy Koreans.
Result and conclusion:  A significant difference of genotype and allele frequencies at PRNP 1368 was found between the normal Korean population and various European populations. In contrast to the results in the British and German populations, our study does not show a significant difference in genotype ( P =  0.2763) and allele ( P  =   0.3750) frequencies of PRNP 1368 between sporadic CJD and normal controls.     

FOXP2, APOE, and PRNP: new modulators in primary progressive aphasia

Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development.     

Polymorphisms at codons 129 and 219 of the prion protein gene (PRNP) are not associated with sporadic Alzheimer's disease in the Korean population

Polymorphisms of prion protein gene ( PRNP ) at codons 129 and 219 play an important role in the susceptibility to Creutzfeldt-Jakob disease (CJD). Alzheimer's disease (AD) and prion diseases, such as CJD, are both characterized by the accumulation of abnormally folded proteins in the brain. An association between sporadic AD and the PRNP polymorphism at codon 129 has been reported in several studies, but other studies have failed to confirm an association. To investigate whether PRNP polymorphisms are associated with an increased risk for developing sporadic AD in the Korean population, we compared the genotype, allele, and haplotype frequencies of PRNP polymorphisms in 271 sporadic AD patients with those in 236 healthy Koreans. Our study does not show a significant difference in PRNP genotype, allele, and haplotype frequency at codons 129 and 219 between sporadic AD and normal controls. Analyses stratifying by age at disease onset, and gender also failed to reveal any association between these polymorphisms and sporadic AD. These results indicate that these PRNP polymorphisms have no direct influence on the susceptibility to sporadic AD in the Korean population.     

Epidemiology of Creutzfeldt-Jakob disease—past and present uncertainties

Annual incidence rate of Creutzfeldt-Jakob disease (CJD) is approximately equal to one per million. Because of misdiagnosis, especially in older individuals, and censoring by competitive cause of death, the true incidence of the disease might be underestimated. Incidence rates of CJD increased in all countries during the last 20 years; this increase is likely due to greater interest in this disease. Foci have been described in Lybian Jews in Israel and Slovakia; in these foci the codon 200 mutation of the PRNP gene was found in all CJD cases. Up to now, no CJD focus which might be explained by environmental exposure has ever been documented. Overall, about 85% of CJD cases are sporadic and 15% are associated with different mutations of the PRNP gene. More than half of CJD cases with PRNP mutation have no known family history of CJD. About 100 iatrogenic CJD cases have been published; most have been related to human growth hormone treatment. The causes of sporadic CJD are unknown. Except the codon 129 polymorphism of the PRNP gene, there are no well established risk factors for sporadic CJD. The recent occurence of a new variant of CJD which might be linked with bovine spongiform encephalopathy raises new issues about the role of environmental exposures in sporadic CJD.     

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.     

A rapid and efficient method for the detection of point mutations of the human prion protein gene (PRNP) by direct sequencing

Creutzfeldt-Jakob disease (CJD) and related disorders occur in sporadic, acquired and inherited forms. In sporadic, iatrogenic and new variant CJD the polymorphic codon 129 of the prion protein gene (PRNP) plays an important role for the susceptibility to the disease and for the clinical and neuropathological manifestations. All the inherited forms of CJD and related disorders are linked to point or insert mutations of PRNP. The analysis of PRNP is therefore important for a correct classification of these disorders and for the identification of novel mutations. The aim of the present study is to describe a fast and easy to perform method for the direct sequencing of the PCR amplified PRNP open reading frame, by using M13 tailed primers which allow a direct and rapid method of sequencing. The goodness of this method is demonstrated in the analysis of three sporadic CJD patients with different genotypes at codon 129 and three inherited cases bearing different point mutations of PRNP: the Pro102Leu mutation linked to Gerstmann-Str?ussler-Scheinker-syndrome, the Val210Ile mutation and a novel mutation at codon 211 (Gln211Glu) both associated to familial CJD.     

PRNP M129V homozygosity in multiple system atrophy vs. Parkinson’s disease

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown etiology characterized by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination. We report a patient with a 4-year history of MSA who developed dementia associated with sporadic Creutzfeldt–Jakob disease (CJD). Our proband was MM homozygous for the M129V polymorphism within the prion protein gene (PRNP), a known risk factor for CJD. We conducted a case–control study to test the hypothesis that homozygosity for the M129V polymorphism of PRNP occurs more frequently in MSA in comparison to Parkinson’s disease and healthy volunteers. A total of 63 patients with MSA, 54 age-, race- and gendermatched controls with Parkinson’s disease, and 126 matched healthy volunteers were studied. The genotype analysis revealed no significant difference in the codon 129 genotype distribution in MSA as compared to controls. Nonetheless, the frequencies of the MM and VV genotypes were higher in MSA than in Parkinson’s disease. Thus, homozygosity, particularly VV homozygosity, at codon 129 of PRNP is associated with MSA compared to a clinically related but pathophysiologically distinct α-synucleinopathy. Considering the possibility that the prion protein contributes to the pathogenesis of MSA would require confirmation of these findings in an independent patient population.     

Cluster of Creutzfeldt–Jakob disease in France associated with the codon 200 mutation (E200K) in the prion protein gene

Between 1992 and 1995, the annual incidence of Creutzfeldt–Jakob disease (CJD) in one of the 96 French départments (adminstrative districts) was found to be about six times higher than the CJD national incidence. Among the 12 definite or probable CJD patients referred during this period within this département , nine originated from a small confined area (30 × 30 km) and seven patients carried the E200K mutation in their prion protein gene ( PRNP ). Genealogical data showed that these seven cases, together with three other ones previously referred during the 1970–82 period, probably belonged to different branches of the same family which could be traced to the beginning of the eighteenth century. Interestingly enough, all but two patients presented as sporadic cases before the genealogic and genetic studies. To our knowledge, this study is the first describing in France a focal accumulation of CJD associated with the PRNP E200K mutation.     

The 129 codon polymorphism of the Prion Protein gene influences earlier cognitive performance in Down syndrome subjects

Recently, a frequent prion protein gene (PRNP) polymorphism consisting of a methionine (M) for valine (V) substitution at codon 129 has been associated with cognitive impairment in elderly individuals. Down syndrome (DS) is associated with mental retardation and development of Alzheimer-like brain abnormalities. In the present study, we investigated the role of the PRNP polymorphism in 122 relatively young Italian DS patients. Allele frequencies of DS subjects did not differ from those in the general population. However, we found a significantly faster rate of decline in intellectual ability in the subgroup of DS patients carrying at least one V allele compared with the M/M DS subjects. An additive deleterious effect of apolipoprotein E ɛ4 allele was detected after stratifying by APOE gene status. Our findings provide evidence that variability of the PRNP gene at codon 129 might contribute to accelerating the rate of earlier cognitive decline in DS subjects. Received: 10 May 2002, Received in revised form: 17 December 2002, Accepted: 9 January 2003 Correspondence to: Dr. R. Del Bo