安徽地区汉族家族性肥厚型心肌病MYH7基因突变研究
摘要
背景:家族性肥厚型心肌病(familial hypertrophic cardiomyopathy,FHC)是一种心肌肌小节基因相关疾病,单一责任基因突变即可致病。患者可在无明显诱因下出现心室肥厚、黑朦、晕厥、心绞痛、心功能不全和猝死。发病人群中家族性发病者约为55%,符合常染色体显性遗传规律,近年来国内外针对FHC的临床和基础研究已步入分子生物学水平,已发现FHC有至少15种致病责任基因,其中β肌球蛋白重链(MYH7)是肌小节的主要成分之一,30%-50%的FHC是由MYH7基因突变所致。而目前有关安徽地区FHC的基因分布和基因突变数据库尚未见系统研究。
目的:目前针对安徽地区FHC致病基因分布、基因型等研究报告较少。我们选择MYH7基因为候选基因,对安徽汉族FHC家系MYH7基因进行测序研究和分析,研究安徽地区FHC的致病基因突变位点和分布,并结合其临床表现,探索MYH7基因型与表现型之间的关系。在此基础上建立临床前期诊断的新方法、新技术,做到早期预防,以期在临床症状出现前即作出患病风险预测及预后估计。
方法:收集3个无血缘关系的汉族家族性肥厚型心肌病的家系(成员共计37人),均来自安徽地区,3例先证者均为男性,年龄42-51岁。每例患者其家族中至少两人发病。对照组为5例健康志愿者(均为安徽汉族,男3例,女2例,42-66岁,各项检查均未见异常)。用碘化钾法常规提取外周静脉血白细胞DNA,于-20℃保存。根据文献报道设计MYH7基因3-26号外显子含侧翼内含子序列的引物。聚合酶链反应(PCR)扩增3例家族性肥厚型心肌病先证者基因组DNA,将所扩增的外显子的PCR产物均按双脱氧末端终止法进行测序反应,应用具有突变位点的目的片段的扩增引物序列,扩增突变先证者家系中其他成员和5例正常人的的DNA目的片段(无论是否诊断为HCM),PCR产物按双脱氧末端终止法进行测序反应。运用chromas程序及Nucleic Acids Research提供的正常人MYH7基因外显子标准序列(genebank)来分析、对照测序结果,检测确定突变位点。
结果:在3个FHC家系先证者中,发现一先证者MYH7基因发生移码突变,其18外显子nt2013(基因组12624位)C缺失、nt2025(基因组12636位)C插入,从而导致其第671位氨基酸发生同义突变即精氨酸(CGC)→精氨酸(CGT),其后续氨基酸均发生编码错误,表达异常蛋白。随后对其家系进行突变筛选,结果在其先证者家系中又发现2例携带该突变,其中1人发病。正常对照组则未发现此突变。
结论:首次在我国汉族人中发现MYH7基因18号外显子nt2013C缺失、nt2025C插入移码突变,此突变在该家系表现为终生外显率较高,发病较晚,多数中年以下者病情相对较轻,无晕厥史,有的年青人尚可无症状。
在3个FHC研究中,发现1个家系为MYH7基因基因的突变,另外2个家系未发现同样突变,反应了HCM的遗传异质性。
具有相同突变的家系成员可有不同表型,临床表型差异较大,提示可能有一些环境因素、修饰基因因素等参与了FHC的发生与发展过程,这些因素可能是造成这些临床表型差异的主要原因。
Background:Hypertrophic cardiomyopathy(HCM) is inherited as a Mendelian autosomal dominant trait;about 55%HCM patients have familial history.Clinical manifestations involve ventricular hypertrophy,especially ventricular septum asymmetric hypertrophy,cardiac arrhythmia,exercise intolerance and sudden death. Generally,encoded cardiac sarcomere genes mutations are molecular mechanisms of HCM.At present,15 encoding cardiac sarcomere genes which mutations caused HCM have already been found.MYH7 gene mutations account for 30%-50%.There are more than 1 million patients with hypertrophic cardiomyopathy(HCM) in China. But the distribution of site mutation of FHC gene in domestic is unknown.This research selected MYH7 to be candidate gene.Three HCM families were subjected for the study.Through proband genome DNA to be sequenced Directly,we would knowledge FHC mutations and the correlation between genotype and phenotype.in Anhui.
Objective:The purpose of the study is to scan the disease-causing gene mutations of MYH7 gene patients with FHC in AnHui and to knowledge mutation site distribution of MYH7 gene.The correlation between genotype and phenotype is also analyzed.
Methods:Three unrelated HCM families of han race and five normal controls came from Anhui province were enrolled in this study.The normal controls involved 3 males and 2 females,with age ranged from 42 to 66 years.Three scattered HCM patients3 males,0 females,aged 42 to 51 years,All subject were examined by echocardiography and electrocardiography(ECG).Clinical data included physical examination,ECG,two-dimensional echocardiography and Doppler echocardiography. ventricular septum or ventricular wall thickness≥15 mm,absence of another cardiac or systemic disease.FHC patients were defined,as there were at least two patients in the same family.No abnormality was seen with respect to physical examination.The exon in the functional regions of the MYH7 gene were amplified with PCR and the products were sequenced.The relation between the genotype and phenotype was analyzed.
Results:Three families probands have the MYH7 gene missense mutation. Sequencing results diplayed:the nt2013 C reduce and nt2025 C insert in mutation were identified in exonl 8 of MYH7 gene in one pedigree.The controls were normal in the genetic test.
Conclusions:This study had confirmed 1 mutations of MYH7 gene among 3 FHC families.MYH7 accounts for 30%.It was identical to foreign reports.The other families had not been found any disease-cause mutation of MYH7.It reflected that HCM have genetic heterogeneity.In this study,the nt2013 C reduce and nt2025 C insert in mutation that identified firstly in Chinese.MYH7 mutations were associated with HCM in the FHC patients of Anhui province.In one family,the identical mutation has different phenotypes and prognoses,and identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of FHC.
目的:目前针对安徽地区FHC致病基因分布、基因型等研究报告较少。我们选择MYH7基因为候选基因,对安徽汉族FHC家系MYH7基因进行测序研究和分析,研究安徽地区FHC的致病基因突变位点和分布,并结合其临床表现,探索MYH7基因型与表现型之间的关系。在此基础上建立临床前期诊断的新方法、新技术,做到早期预防,以期在临床症状出现前即作出患病风险预测及预后估计。
方法:收集3个无血缘关系的汉族家族性肥厚型心肌病的家系(成员共计37人),均来自安徽地区,3例先证者均为男性,年龄42-51岁。每例患者其家族中至少两人发病。对照组为5例健康志愿者(均为安徽汉族,男3例,女2例,42-66岁,各项检查均未见异常)。用碘化钾法常规提取外周静脉血白细胞DNA,于-20℃保存。根据文献报道设计MYH7基因3-26号外显子含侧翼内含子序列的引物。聚合酶链反应(PCR)扩增3例家族性肥厚型心肌病先证者基因组DNA,将所扩增的外显子的PCR产物均按双脱氧末端终止法进行测序反应,应用具有突变位点的目的片段的扩增引物序列,扩增突变先证者家系中其他成员和5例正常人的的DNA目的片段(无论是否诊断为HCM),PCR产物按双脱氧末端终止法进行测序反应。运用chromas程序及Nucleic Acids Research提供的正常人MYH7基因外显子标准序列(genebank)来分析、对照测序结果,检测确定突变位点。
结果:在3个FHC家系先证者中,发现一先证者MYH7基因发生移码突变,其18外显子nt2013(基因组12624位)C缺失、nt2025(基因组12636位)C插入,从而导致其第671位氨基酸发生同义突变即精氨酸(CGC)→精氨酸(CGT),其后续氨基酸均发生编码错误,表达异常蛋白。随后对其家系进行突变筛选,结果在其先证者家系中又发现2例携带该突变,其中1人发病。正常对照组则未发现此突变。
结论:首次在我国汉族人中发现MYH7基因18号外显子nt2013C缺失、nt2025C插入移码突变,此突变在该家系表现为终生外显率较高,发病较晚,多数中年以下者病情相对较轻,无晕厥史,有的年青人尚可无症状。
在3个FHC研究中,发现1个家系为MYH7基因基因的突变,另外2个家系未发现同样突变,反应了HCM的遗传异质性。
具有相同突变的家系成员可有不同表型,临床表型差异较大,提示可能有一些环境因素、修饰基因因素等参与了FHC的发生与发展过程,这些因素可能是造成这些临床表型差异的主要原因。
Background:Hypertrophic cardiomyopathy(HCM) is inherited as a Mendelian autosomal dominant trait;about 55%HCM patients have familial history.Clinical manifestations involve ventricular hypertrophy,especially ventricular septum asymmetric hypertrophy,cardiac arrhythmia,exercise intolerance and sudden death. Generally,encoded cardiac sarcomere genes mutations are molecular mechanisms of HCM.At present,15 encoding cardiac sarcomere genes which mutations caused HCM have already been found.MYH7 gene mutations account for 30%-50%.There are more than 1 million patients with hypertrophic cardiomyopathy(HCM) in China. But the distribution of site mutation of FHC gene in domestic is unknown.This research selected MYH7 to be candidate gene.Three HCM families were subjected for the study.Through proband genome DNA to be sequenced Directly,we would knowledge FHC mutations and the correlation between genotype and phenotype.in Anhui.
Objective:The purpose of the study is to scan the disease-causing gene mutations of MYH7 gene patients with FHC in AnHui and to knowledge mutation site distribution of MYH7 gene.The correlation between genotype and phenotype is also analyzed.
Methods:Three unrelated HCM families of han race and five normal controls came from Anhui province were enrolled in this study.The normal controls involved 3 males and 2 females,with age ranged from 42 to 66 years.Three scattered HCM patients3 males,0 females,aged 42 to 51 years,All subject were examined by echocardiography and electrocardiography(ECG).Clinical data included physical examination,ECG,two-dimensional echocardiography and Doppler echocardiography. ventricular septum or ventricular wall thickness≥15 mm,absence of another cardiac or systemic disease.FHC patients were defined,as there were at least two patients in the same family.No abnormality was seen with respect to physical examination.The exon in the functional regions of the MYH7 gene were amplified with PCR and the products were sequenced.The relation between the genotype and phenotype was analyzed.
Results:Three families probands have the MYH7 gene missense mutation. Sequencing results diplayed:the nt2013 C reduce and nt2025 C insert in mutation were identified in exonl 8 of MYH7 gene in one pedigree.The controls were normal in the genetic test.
Conclusions:This study had confirmed 1 mutations of MYH7 gene among 3 FHC families.MYH7 accounts for 30%.It was identical to foreign reports.The other families had not been found any disease-cause mutation of MYH7.It reflected that HCM have genetic heterogeneity.In this study,the nt2013 C reduce and nt2025 C insert in mutation that identified firstly in Chinese.MYH7 mutations were associated with HCM in the FHC patients of Anhui province.In one family,the identical mutation has different phenotypes and prognoses,and identical mutation might result in different phenotypes suggesting that multiple factors might be involved in the pathogenesis of FHC.
引文
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