脊髓小脑性共济失调2型患者的临床特点及ATXN2基因突变分析

发布时间：2018-02-07 14:05

本文关键词： 脊髓小脑性共济失调2型帕金森病 ATXN2基因三核苷酸重复　出处：《中南大学》2014年硕士论文　论文类型：学位论文

【摘要】：背景：脊髓小脑性共济失调2型(SCA2)是一种常染色体显性遗传脊髓小脑性共济失调亚型(AD-SCA),其致病是位于12q23-24染色体上的ATXN2基因1号外显子的CAG三核苷酸异常重复扩增所致。SCA2占SCA患病总人数的3%-47%,在意大利、英国、印度等国家常见,主要临床表现为运动协调功能障碍,部分患者可合并锥体外系表现。目的：了解SCA2在中国大陆SCA患病人群中的频率分布；研究ATXN2基因CAG三核苷酸重复与中国大陆家族性帕金森病(PD)的关联；进一步了解SCA2及PD-SCA2患者临床特点及ATXN2基因CAG三核苷酸重复次数、重复序列打断情况对SCA2、PD-SCA2患者临床表型的影响。方法：对713个常染色体显性遗传SCA家系、444名散发SCA患者及75个常染色体显性遗传PD家系进行临床总结,应用PCR扩增、变性聚丙烯酰胺凝胶电泳、毛细管凝胶电泳及T载体连接克隆测序等方法进行ATXN2基因CAG三核苷酸重复次数及序列测定,并运用Mann-Whitney U检验、线性回归分析法等对结果进行统计分析。结果：在713个AD-SCA家系中检测出59个SCA2家系(8.28%),在444名S-SCA患者中检测出10名SCA2患者(2.25%)；在75个常染色体显性遗传PD家系中检测出6个PD-SCA2家系(8%)；SCA2患者临床表现多样,锥体外系症状较常见,PD-SCA2患者起病年龄大于SCA2患者组,大多不伴有共济失调表现且抗帕金森病药物有效；PD-SCA2患者的ATXN2基因CAG三核苷酸重复次数明显偏小,和SCA2患者存在显著差异； SCA2患者中ATXN2基因CAG三核苷酸重复次数与患者发病年龄呈负相关,贡献度为58.9%,PD-SCA2患者中则无此规律；SCA2患者组ATXN2基因CAG三核苷酸重复序列以无CAA打断最常见(85.71%),PD-SCA2患者组及正常对照组则以1到2次CAA打断最常见,分别占76.92%和93%,三组重复序列CAA打断模式两两间均存在显著差异； SCA2患者组的3’端CAG三核苷酸重复序列结尾时被1次CCG打断最常见(38.46%),PD-SCA2患者组及正常对照组则以无CCG打断最常见,分别占92.31%和100%。SCA2患者组与正常对照组、SCA2患者组与PD-SCA2患者组的3’端CCG打断模式有显著差异,但PD-SCA2患者组与正常对照组间无显著差异。结论： 1、SCA2是中国汉族SCA家系中除SCA3外最常见亚型,在常染色体显性遗传家系中占8.28%,在散发患者中占2.25%； 2、ATXN2基因异常重复扩增可导致帕金森样表型,ATXN2基因可能是中国汉族家族性PD的致病基因； 3.ATXN2基因CAG三核苷酸重复次数、重复序列CAA打断模式及3’端CCG打断模式可能与SCA2及PD-SCA2患者表型有关。
[Abstract]:Background: Spinal cerebellar ataxia type 2 (SCA2) is an autosomal dominant spinal cerebellar ataxia subtype AD-SCA2, which causes abnormal CAG trinucleotide amplification of exon 1 of ATXN2 gene on chromosome 12q23-24. SCA2 accounted for 3%-47% of the total number of patients with SCA, in Italy, In Britain, India and other countries, the main clinical manifestation is motor coordination dysfunction, some patients can be combined with extrapyramidal system. Objective: to investigate the frequency distribution of SCA2 in the population with SCA in mainland China, and to study the association between CAG trinucleotide repeat of ATXN2 gene and familial Parkinson's disease (PD) in mainland China. To investigate the clinical characteristics of SCA2 and PD-SCA2 patients and the influence of CAG trinucleotide repeats of ATXN2 gene on the clinical phenotypes of patients with SCA2P PD-SCA2. Methods: 444 autosomal dominant SCA pedigrees and 75 autosomal dominant PD families were analyzed by PCR amplification and denatured polyacrylamide gel electrophoresis. Capillary gel electrophoresis (CE) and T-vector ligation cloning and sequencing were used to determine the CAG trinucleotide repeat number and sequence of ATXN2 gene. Mann-Whitney U test and linear regression analysis were used to analyze the results. Results: 59 SCA2 families were detected in 713 AD-SCA families, 10 out of 444 S-SCA patients with SCA2, and 6 PD-SCA2 families in 75 autosomal dominant PD families. The onset age of PD-SCA2 patients with common extrapyramidal symptoms was higher than that of SCA2 patients, and most of them had no ataxia and the ATXN2 gene CAG trinucleotide repeats of PD-SCA2 patients with effective antiParkinson disease drugs were significantly smaller than those of SCA2 patients. The number of ATXN2 gene CAG trinucleotide repeats in SCA2 patients was negatively correlated with the age of onset. The ATXN2 gene CAG trinucleotide repeat sequence in the SCA2 group was the most common in the PD-SCA2 patient group and the normal control group with one or two CAA interruptions with no CAA interrupting the CAG trinucleotide repeat sequence in the PD-SCA2 patients and in the normal control group, and the results showed that the CAG trinucleotide repeat sequence of the ATXN2 gene was most common in the patients with PD-SCA2 and in the normal control group. 76.92% and 93%, respectively. There were significant differences between the two groups of repeated sequence CAA interruption patterns. The 3'end CAG trinucleotide repeat at the end of the 3'end of the SCA2 group was most frequently interrupted by once CCG. The most common interruption was no CCG in the PD-SCA2 patient group and the normal control group. The 3'end CCG interruption pattern in SCA2 group and normal control group was significantly different from that in PD-SCA2 group, but there was no significant difference between PD-SCA2 group and normal control group. Conclusion:. 1SCA2 is the most common subtype of SCA in Chinese Han nationality, except SCA3, which accounts for 8.28% in autosomal dominant families and 2.25% in sporadic patients. 2abnormal repeat amplification of ATXN2 gene may lead to Parkinson's like phenotypic gene ATXN2 gene may be the pathogenic gene of Chinese Han nationality familial PD. 3. The number of CAG trinucleotide repeats in ATXN2 gene, the CAA interruption pattern of repeat sequence and the 3'terminal CCG interruption pattern may be related to the phenotypes of SCA2 and PD-SCA2 patients.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R744.7

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