脊髓小脑共济性失调2型的修饰基因变异及自然选择对ATXN2基因的影响
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摘要
本研究室收集到一个表型为帕金森氏病的大家系,临床资料初步诊断为呈常染色体显性遗传模式的帕金森氏病家系。前期对此家系进行的研究排除了以往文献报道过的常染色体显性遗传的帕金森病致病基因,并采用基因芯片的方法对研究家系进行了全基因组扫描,最后在患者基因组候选区域内将致病基因定位为12号染色体上的ATXN2基因,确定该家系为脊髓小脑共济性失调2型(spinocerebellar ataxia type 2,SCA2)家系。
SCA2是一种山ATXN2基因第一外显子中的CAG三核苷酸扩展突变导致的神经系统退行性疾病,发病时严重影响正常的感觉、运动控制功能。由于本家系病人表现出和普通SCA2病人不同的临床症状,并且对左旋多巴胺(L-Dopa)的治疗敏感,因而在本研究中,我们应用前期全基因组扫描的数据,按照所收集家系的临床资料对疾病表型模式进行设定,重新计算了连锁值。结果发现有两处连锁分数值(log of the odds,LOD)大于3：一处在5号染色体上,另一处在12号染色体上的峰对应的就是本家系的致病基因ATXN2。根据以上结果,我们对5号染色体的定位区域进行了单倍型构建及分析,进而观察到所有现在已经确定发病的病人基本都享有同样条单倍型,即3322323单倍型。据此推测可能在5号染色体上这一定位区域存在个修饰基因,使此家系的发病症状偏向于帕金森氏病,并且让发病年龄提前。我们用测序的方法,对所定位区域内的5个修饰基因候选者——-ENC1,HEXB,SV2C,GFM2以及HOMER1进行研究,从而寻找修饰基因的存在,用以分析探讨此修饰基因怎样使SCA2病人临床症状发生改变,并使本研究家系成员对多巴胺敏感的原因。检测结果显示,在HEXB基因第五外显子上存在一处第207位氨基酸ATT/GTT错义突变,从本研究家系测序结果分布看来,所有的病人都带有A等位基因；在ENC1的5'-UTR区发现一A/G突变以及在其外显子的分段测序中检到两处同义突变(分别为丝氨酸、赖氨酸同义突变),据家系中5'-UTR区测序结果看来,绝大部分病人都带有A等位基因。而其余三个基因均未观察到突变。根据以上结果分析,我们认为HEXB基因的错义突变为本研究寻找的修饰基因变异的可能性较大。由于各个基因间相互作用的关系非常复杂,修饰基因的突变位点可能与其他位点连锁共同作用,基因的同义突变也可能影响转录后的剪接、加工及蛋白表达量进而影响疾病表型,或者存在其他未经鉴定的复杂作用过程或基因,这些功能上的作用及机制需要进一步阐明。
有研究认为帕金森表型的出现和ATXN2基因CAG重复中CAA三核苷酸插入出现的频率有关,我们通过对本家系中致病基因序列的测定,对其关联性加以验证。在本家系的病人中检测到ATXN2基因CAG重复序列中仅有一个CAA插入,与文献报道的病人CAA插入次数越多表型就越偏向帕金森病不一致,提示可能存在其他因素对本家系产生影响,使之对左旋多巴敏感。因此,本研究选取6个正常民族群体,对其ATXN2基因的CAG重复序列是否受到选择的作用进行研究,以期闸明致病基因的作用机制及其与自然选择的关系。
我们对所有样本染色体的CAG重复序列进行了测序。进行中性检测后发现,在除了回族群体以外的5个民族群体中,Tajima's D值显示了显著性的负值,提示可能受到正向选择的作用。回族群体的中性检测值仅显示为负值,未达到显著性。根据该位点周围8个SNP的分型结果构建单倍型进行分析,也显示核心单倍型达到了很高的频率,并在一个较大的区域内显示了强连锁不平衡(linkage disequilibrium, LD)。这些都是5个民族群体中正向选择的特征。我们认为在这5个民族群体ATXN2基因的CAG重复序列上可能存在正向选择的作用,使(CAG)8CAA(CAG)4CAA(CAG)8这种等位基因在正常群体中具有优势,保持遗传稳定而不趋于扩展。同时也提示我们,其他的多聚谷氨酰胺(polyglutamine, polyQ)相关疾病致病基因可能也存在类似的机制,对于这些致病基因是否受到选择的作用,值得我们进一步的研究。
A Parkinsonism pedigree was collected by our group. According to clinical characteristics, primary diagnosis showed that it was an autosomal dominant (AD) Parkinson Disease pedigree. The known pathogenic genes of AD Parkinson Disease were excluded in our previously study and a whole genomic scan was performed by gene chip. The pathogenic gene ATXN2 was located on chromosome 12, the candidate region of patient's genome. Thereby, this pedigree was finally confirmed as a Spinocerebellar Ataxia type 2 (SCA2) family.
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by the expansions of CAG trinucleotide repeat in exon 1 of the ATXN2 gene, which has severe influences on sensory and motor controlling functions. Because the patients exhibited different clinical phenotypes in this family with other common type of SCA2 and were sensitive to levodopa treatment, thus, to investigate whether modifier genes exist, log of the odds (LOD) were recomputed according to the settings of this SCA2 family phenotype mode using the preliminary work data of the whole genomic scan. The results showed that two LOD scores were more than 3, one scroe existed on chromosome 5, another was on chromosome 12, where the SCA2 pathogenic gene ATXN2 located at. Subsequently, haplotypes were constructed and analyzed in the location region on chromosome 5 depending on the results above. The same haplotype "3322323" was exhibited among almost all of the patients. Based on these, we presumed that modifier genes existed in this region of chromosome 5, which made the clinical phenotype deviation in favor of Parkinson Disease trails and age of onset ahead of time. Therefore, DNA sequencing was operated on five candidate genes in the location region of chromosome 5 for the purpose of finding whether these modifier genes exist, so as to discuss how modifier genes made SCA2 patients'clinical symptoms changed and to find the reasons for responsing to levodopa. The results showed that a missense mutation ATT/GTT existed on 207 amino acid of the HEXB gene exon 5. From the distributions of this mutation in the pedigree, A allele was carried in all of the patients. Furthermore, A/G mutation in 5'-UTR and two synonymy mutations (serine and lysine, respectively) were detected in ENC1 gene. According to results of 5'-UTR, almost all of the patients carried with A allele. Moreover, no mutation was observed in the other three genes. According to these results above, we considered that the missense mutation of the HEXB gene could be the modifier gene variation in this research which had more possibilities. On account of complex interactional relationships between genes, the mutations of modifier genes could have combined action with other locus. A synonymy mutation also could influence RNA post-transcriptional splicing, processing and the expression of protein, and then affect the phenotype. Perhaps other unidentified complex mechanism and genes exist. These mechanisms need to be clarified.
Some researches proposed that the appearance of Parkinsonism in SCA2 patients was associated with frequency of CAA interuptions in CAG repeats of the ATXN2 gene. This association was analyzed by sequencing the CAG repeats. There was only one CAA interruption detected in the CAG repeats of ATXN2 gene in patients of our pedigree, which was discord with the reports that more CAA interruptions made the phenotype in favor of Parkinson Disease. It prompted other factors could have impacts on this family and made them sensitive to levodopa. Therefore, to investigate whether this CAG repeat of the ATXN2 gene is under positive selection, we collected six different Chinese ethnic groups, to evaluate the mechanism of the pathogenic gene and the relation with natural selection.
The segments containing CAG repeats in the ATXN2 gene were sequenced for all chromosomes. Significantly negative Tajima's D values were observed in 5 ethnic groups except Hui by performing neutral tests, which suggested positive selection could act on this locus. Hui only showed negative values in these tests, but not significant. Haplotypes were constructed with genotyping data of 8 adjacent SNPs, which also demonstrated that core haplotype reached a high frequency and strong linkage disequilibrium reflected in a large region. These are signatures for positive selection in these 5 ethnic groups. We proposed that positive selection could act on this CAG repeat in these five ethnic groups and make (CAG)8CAA(CAG)4CAA(CAG)8 allele predominant in normal groups, which keeps heredity stability from expanding. Meanwhile, it was suggested that disease causing genes of other polyQ diseases probably have similar mechanism. Whether these related genes are under positive selection or not is worth further investigating.
SCA2是一种山ATXN2基因第一外显子中的CAG三核苷酸扩展突变导致的神经系统退行性疾病,发病时严重影响正常的感觉、运动控制功能。由于本家系病人表现出和普通SCA2病人不同的临床症状,并且对左旋多巴胺(L-Dopa)的治疗敏感,因而在本研究中,我们应用前期全基因组扫描的数据,按照所收集家系的临床资料对疾病表型模式进行设定,重新计算了连锁值。结果发现有两处连锁分数值(log of the odds,LOD)大于3：一处在5号染色体上,另一处在12号染色体上的峰对应的就是本家系的致病基因ATXN2。根据以上结果,我们对5号染色体的定位区域进行了单倍型构建及分析,进而观察到所有现在已经确定发病的病人基本都享有同样条单倍型,即3322323单倍型。据此推测可能在5号染色体上这一定位区域存在个修饰基因,使此家系的发病症状偏向于帕金森氏病,并且让发病年龄提前。我们用测序的方法,对所定位区域内的5个修饰基因候选者——-ENC1,HEXB,SV2C,GFM2以及HOMER1进行研究,从而寻找修饰基因的存在,用以分析探讨此修饰基因怎样使SCA2病人临床症状发生改变,并使本研究家系成员对多巴胺敏感的原因。检测结果显示,在HEXB基因第五外显子上存在一处第207位氨基酸ATT/GTT错义突变,从本研究家系测序结果分布看来,所有的病人都带有A等位基因；在ENC1的5'-UTR区发现一A/G突变以及在其外显子的分段测序中检到两处同义突变(分别为丝氨酸、赖氨酸同义突变),据家系中5'-UTR区测序结果看来,绝大部分病人都带有A等位基因。而其余三个基因均未观察到突变。根据以上结果分析,我们认为HEXB基因的错义突变为本研究寻找的修饰基因变异的可能性较大。由于各个基因间相互作用的关系非常复杂,修饰基因的突变位点可能与其他位点连锁共同作用,基因的同义突变也可能影响转录后的剪接、加工及蛋白表达量进而影响疾病表型,或者存在其他未经鉴定的复杂作用过程或基因,这些功能上的作用及机制需要进一步阐明。
有研究认为帕金森表型的出现和ATXN2基因CAG重复中CAA三核苷酸插入出现的频率有关,我们通过对本家系中致病基因序列的测定,对其关联性加以验证。在本家系的病人中检测到ATXN2基因CAG重复序列中仅有一个CAA插入,与文献报道的病人CAA插入次数越多表型就越偏向帕金森病不一致,提示可能存在其他因素对本家系产生影响,使之对左旋多巴敏感。因此,本研究选取6个正常民族群体,对其ATXN2基因的CAG重复序列是否受到选择的作用进行研究,以期闸明致病基因的作用机制及其与自然选择的关系。
我们对所有样本染色体的CAG重复序列进行了测序。进行中性检测后发现,在除了回族群体以外的5个民族群体中,Tajima's D值显示了显著性的负值,提示可能受到正向选择的作用。回族群体的中性检测值仅显示为负值,未达到显著性。根据该位点周围8个SNP的分型结果构建单倍型进行分析,也显示核心单倍型达到了很高的频率,并在一个较大的区域内显示了强连锁不平衡(linkage disequilibrium, LD)。这些都是5个民族群体中正向选择的特征。我们认为在这5个民族群体ATXN2基因的CAG重复序列上可能存在正向选择的作用,使(CAG)8CAA(CAG)4CAA(CAG)8这种等位基因在正常群体中具有优势,保持遗传稳定而不趋于扩展。同时也提示我们,其他的多聚谷氨酰胺(polyglutamine, polyQ)相关疾病致病基因可能也存在类似的机制,对于这些致病基因是否受到选择的作用,值得我们进一步的研究。
A Parkinsonism pedigree was collected by our group. According to clinical characteristics, primary diagnosis showed that it was an autosomal dominant (AD) Parkinson Disease pedigree. The known pathogenic genes of AD Parkinson Disease were excluded in our previously study and a whole genomic scan was performed by gene chip. The pathogenic gene ATXN2 was located on chromosome 12, the candidate region of patient's genome. Thereby, this pedigree was finally confirmed as a Spinocerebellar Ataxia type 2 (SCA2) family.
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by the expansions of CAG trinucleotide repeat in exon 1 of the ATXN2 gene, which has severe influences on sensory and motor controlling functions. Because the patients exhibited different clinical phenotypes in this family with other common type of SCA2 and were sensitive to levodopa treatment, thus, to investigate whether modifier genes exist, log of the odds (LOD) were recomputed according to the settings of this SCA2 family phenotype mode using the preliminary work data of the whole genomic scan. The results showed that two LOD scores were more than 3, one scroe existed on chromosome 5, another was on chromosome 12, where the SCA2 pathogenic gene ATXN2 located at. Subsequently, haplotypes were constructed and analyzed in the location region on chromosome 5 depending on the results above. The same haplotype "3322323" was exhibited among almost all of the patients. Based on these, we presumed that modifier genes existed in this region of chromosome 5, which made the clinical phenotype deviation in favor of Parkinson Disease trails and age of onset ahead of time. Therefore, DNA sequencing was operated on five candidate genes in the location region of chromosome 5 for the purpose of finding whether these modifier genes exist, so as to discuss how modifier genes made SCA2 patients'clinical symptoms changed and to find the reasons for responsing to levodopa. The results showed that a missense mutation ATT/GTT existed on 207 amino acid of the HEXB gene exon 5. From the distributions of this mutation in the pedigree, A allele was carried in all of the patients. Furthermore, A/G mutation in 5'-UTR and two synonymy mutations (serine and lysine, respectively) were detected in ENC1 gene. According to results of 5'-UTR, almost all of the patients carried with A allele. Moreover, no mutation was observed in the other three genes. According to these results above, we considered that the missense mutation of the HEXB gene could be the modifier gene variation in this research which had more possibilities. On account of complex interactional relationships between genes, the mutations of modifier genes could have combined action with other locus. A synonymy mutation also could influence RNA post-transcriptional splicing, processing and the expression of protein, and then affect the phenotype. Perhaps other unidentified complex mechanism and genes exist. These mechanisms need to be clarified.
Some researches proposed that the appearance of Parkinsonism in SCA2 patients was associated with frequency of CAA interuptions in CAG repeats of the ATXN2 gene. This association was analyzed by sequencing the CAG repeats. There was only one CAA interruption detected in the CAG repeats of ATXN2 gene in patients of our pedigree, which was discord with the reports that more CAA interruptions made the phenotype in favor of Parkinson Disease. It prompted other factors could have impacts on this family and made them sensitive to levodopa. Therefore, to investigate whether this CAG repeat of the ATXN2 gene is under positive selection, we collected six different Chinese ethnic groups, to evaluate the mechanism of the pathogenic gene and the relation with natural selection.
The segments containing CAG repeats in the ATXN2 gene were sequenced for all chromosomes. Significantly negative Tajima's D values were observed in 5 ethnic groups except Hui by performing neutral tests, which suggested positive selection could act on this locus. Hui only showed negative values in these tests, but not significant. Haplotypes were constructed with genotyping data of 8 adjacent SNPs, which also demonstrated that core haplotype reached a high frequency and strong linkage disequilibrium reflected in a large region. These are signatures for positive selection in these 5 ethnic groups. We proposed that positive selection could act on this CAG repeat in these five ethnic groups and make (CAG)8CAA(CAG)4CAA(CAG)8 allele predominant in normal groups, which keeps heredity stability from expanding. Meanwhile, it was suggested that disease causing genes of other polyQ diseases probably have similar mechanism. Whether these related genes are under positive selection or not is worth further investigating.
引文
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