一个特发性Brugada综合征心电图征家系的分子遗传学分析
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摘要
目的:研究一个湖北的Brugada心电图样改变的患者及其家系成员是否存在基因突变,若存在则分析其突变基因和可能的分子遗传学和电生理机制以及和临床表现心电图特征之间的关系。
方法:收集家族成员的临床资料、心电图和血液标本。从外周血提取她们的白细胞DNA后进行连锁分析,根据连锁反应的结果筛选致病基因,针对可能性最大的致病基因SCN5A设计引物,依次经行聚合酶链反应扩增所有家族成员的28个外显子,琼脂糖凝胶电泳,回收PCR反应产物后进行BigDye单链扩增,纯化扩增产物,直接DNA测序,发现基因突变后应用限制性片段长度多态性技术(Restriction Fragment Length Polymorphism, RFLP),用限制性内切酶对含有和不含有突变的家族成员以及正常人的PCR产物经行酶切反应验证。并进行家系调查分析,分析遗传特点、突变的分布情况以及和心电图改变的关系。
结果:心电图资料显示先证者存在2型Brugada波(马鞍型),其他3位家系成员的心电图分别提示混合型Brugada波和上抬的J波。连锁分析提示SCN5A这个基因的可能性最大。经过DNA测序发现先证者的SCN5A基因的第1001位密码子的第二个碱基处有一个“双峰”,经过数据库的查找发现这是一个错义突变T3002A,导致其所编码的Nav1.5离子通道α-亚单位的DII同源结构域的S5-S6跨膜节段之间的P环上的一个亮氨酸被谷氨酰胺取代(L1001P)。在此家族包括先证者及其3个兄弟姐妹和她的女儿在内共5人的DNA检测到了此突变。对家族所有成员和50个正常人的PCR产物的酶切分析提示正常人不存在此突变。同时在发现突变的家系成员中也发现了3个基因多态。
结论:在中国的一个Brugada心电图样改变的家系发现了一个新的突变位点T3002A,家系中有五名成员检测出此杂合突变,连锁分析、基因测序、酶切反应的结果一致支持Brugada症状是常染色体显性遗传的特点。先证者及其家族成员均无晕厥、夜间濒死呼吸、室颤等临床症状,也无家族成员猝死史,先证者和其3个兄妹以及先证者的女儿仅有不典型的Brugada心电图样改变,但是在基因检测时,上述5人却均在SCN5A的第1001位密码子的第二个碱基处检测到一个杂合突变T3002A,提示可能是环境因素对突变位点导致的钠离子通道功能缺陷的一种修复现象,亦可能是由于基因多态对突变所致的Na+离子通道蛋白表达下降的负性消弱作用;第三种解释是尽管错义突变T3002A使SCN5A编码的蛋白的DII结构域的S5-S6之间的P环上的亮氨酸被谷氨酰胺取代,但是具体对其功能的影响程度有多大,则需要进行细胞功能的研究,比如突变的诱导,转染、膜片钳、动作电位等方面的研究,或许这个突变仅仅部分影响了Na离子通道的通透性和选择性,使钠通道在大多时刻仍然可以维持正常的生理功能,这也许就是先证者及其家属仅仅有心电图的不典型改变而没有任何临床症状的原因。
Objective: To investigate the mutation in a family with Brugada-like electrocardiogram pattern. To analysis the gene mutation and possible mechanism of molecular genetics and electrophysiology if the mutation existed, as well as the connection between mutation and clinical manifestation including ECG features.
Methods: Clinical data, ECGs, and blood samples of 14 family members were collected for later investigation. Genomic DNAs were extracted from peripheral blood of each member. Screening the candidate gene according the result of linkage analysis accompanying with information form documents and database of interenet. 32 pairs of primers were designed for all 28 exons of SCN5A gene which has the best chance to be the disease-causing gene. Amplifying all 28 exons of family members by polymerase chain reactions. Amplifying the recoveryed PCR products by BigDye single-stranded amplification after agarose gel electrophoresis. Direct DNA sequencings were performed after the purification of Single-stranded amplification products. Applying Restriction Fragment Length Polymorphism (RFLP) technology to validate the existence of mutation in all the family members and 50 normal Chinese. Analyzing the genetic features of the family, as well as the distribution of mutation and the relationship between mutation and ECG performances.
Results: A type 2 Brugada ECG pattern (saddleback-like) was showed on ECG data of proband, other ECG results of 3 family members showed type 3 Brugada ECG pattern and elevated J-wave respectively. The result of linkage analysis showed the SCN5A gene could be the most possible candidate gene. Direct DNA sequencing revealed a“double peak”in the second nucleotide of codon 1001 in SCN5A gene of proband, which was identified to be a missense mutation (T3002A) after matching and searching in databases. The T→A replacement at the 3002 site of cDNA of SCN5A causing the substitution of leucine by glutamine(L1001P) in the P-loop of the pore-lining region between transmembrane segments S5-S6 of domain DII, which is one of key structures of Nav1.5 cardiac sodium channelα-subunit. This mutation were found in proband, 3 siblings of proband, the daughter of proband, the restriction enzyme digest analysis of other family members and 50 healthy individuals revealed no same mutation in normals were detected. 3 Single Nucleotide Polymorphisms were detected in family members with mutation at the same time.
Conclusions: A novel mutation T3002A of SCN5A was detected in a Chinese Family with Brugada-like electrocardiogram pattern. 5 members of the family were comfirmed with this heterozygous mutation. The results of linkage analysis, direct sequencing and the restriction enzyme digest analysis unanimously support the characteristic of Brugada syndrome as an autosomal dominant inheritance. No history of syncope; nocturnal agonal respiration; ventricular fibrillation; polymorphic ventricular tachycardia; a family history of sudden death under 45 years old were recorded among family members, the only clinical evidence were atypical Brugada-like electrocardiogram pattern records of proband and her 3 siblings and her daughter. However, when undertook genetic detection, all the 5 family members mention above showed an heterozygous mutation T3002A in the second nucleotide of codon 1001 in SCN5A gene, which suggests the likelihood that the defects in sodium channel function repaired by environmental factors. It is also could be the contribution of negative weakening effect that single nucleotide polymorphism brought on the low expression of sodium channel protein caused by mutation. The third explanation is that despite the missense mutation T3002A led the replacement of leucine by glutamine in the P-loop between transmembrane segments S5-S6 of domain DII of protein encoded by SCN5A,the specific extent of the influence on function is unclear, which require the investigation of cell function, such as mutation induction, transfection, patch clamp, action protentials and other research. It’s likely the mutation only partially affected the permeability and selectivity of sodium channel, which means the channel can still maintain its normal physiological function most of the time. This could explain why proband and other family members only have an asymptomatic and atypical Brugada-like electrocardiogram pattern.
方法:收集家族成员的临床资料、心电图和血液标本。从外周血提取她们的白细胞DNA后进行连锁分析,根据连锁反应的结果筛选致病基因,针对可能性最大的致病基因SCN5A设计引物,依次经行聚合酶链反应扩增所有家族成员的28个外显子,琼脂糖凝胶电泳,回收PCR反应产物后进行BigDye单链扩增,纯化扩增产物,直接DNA测序,发现基因突变后应用限制性片段长度多态性技术(Restriction Fragment Length Polymorphism, RFLP),用限制性内切酶对含有和不含有突变的家族成员以及正常人的PCR产物经行酶切反应验证。并进行家系调查分析,分析遗传特点、突变的分布情况以及和心电图改变的关系。
结果:心电图资料显示先证者存在2型Brugada波(马鞍型),其他3位家系成员的心电图分别提示混合型Brugada波和上抬的J波。连锁分析提示SCN5A这个基因的可能性最大。经过DNA测序发现先证者的SCN5A基因的第1001位密码子的第二个碱基处有一个“双峰”,经过数据库的查找发现这是一个错义突变T3002A,导致其所编码的Nav1.5离子通道α-亚单位的DII同源结构域的S5-S6跨膜节段之间的P环上的一个亮氨酸被谷氨酰胺取代(L1001P)。在此家族包括先证者及其3个兄弟姐妹和她的女儿在内共5人的DNA检测到了此突变。对家族所有成员和50个正常人的PCR产物的酶切分析提示正常人不存在此突变。同时在发现突变的家系成员中也发现了3个基因多态。
结论:在中国的一个Brugada心电图样改变的家系发现了一个新的突变位点T3002A,家系中有五名成员检测出此杂合突变,连锁分析、基因测序、酶切反应的结果一致支持Brugada症状是常染色体显性遗传的特点。先证者及其家族成员均无晕厥、夜间濒死呼吸、室颤等临床症状,也无家族成员猝死史,先证者和其3个兄妹以及先证者的女儿仅有不典型的Brugada心电图样改变,但是在基因检测时,上述5人却均在SCN5A的第1001位密码子的第二个碱基处检测到一个杂合突变T3002A,提示可能是环境因素对突变位点导致的钠离子通道功能缺陷的一种修复现象,亦可能是由于基因多态对突变所致的Na+离子通道蛋白表达下降的负性消弱作用;第三种解释是尽管错义突变T3002A使SCN5A编码的蛋白的DII结构域的S5-S6之间的P环上的亮氨酸被谷氨酰胺取代,但是具体对其功能的影响程度有多大,则需要进行细胞功能的研究,比如突变的诱导,转染、膜片钳、动作电位等方面的研究,或许这个突变仅仅部分影响了Na离子通道的通透性和选择性,使钠通道在大多时刻仍然可以维持正常的生理功能,这也许就是先证者及其家属仅仅有心电图的不典型改变而没有任何临床症状的原因。
Objective: To investigate the mutation in a family with Brugada-like electrocardiogram pattern. To analysis the gene mutation and possible mechanism of molecular genetics and electrophysiology if the mutation existed, as well as the connection between mutation and clinical manifestation including ECG features.
Methods: Clinical data, ECGs, and blood samples of 14 family members were collected for later investigation. Genomic DNAs were extracted from peripheral blood of each member. Screening the candidate gene according the result of linkage analysis accompanying with information form documents and database of interenet. 32 pairs of primers were designed for all 28 exons of SCN5A gene which has the best chance to be the disease-causing gene. Amplifying all 28 exons of family members by polymerase chain reactions. Amplifying the recoveryed PCR products by BigDye single-stranded amplification after agarose gel electrophoresis. Direct DNA sequencings were performed after the purification of Single-stranded amplification products. Applying Restriction Fragment Length Polymorphism (RFLP) technology to validate the existence of mutation in all the family members and 50 normal Chinese. Analyzing the genetic features of the family, as well as the distribution of mutation and the relationship between mutation and ECG performances.
Results: A type 2 Brugada ECG pattern (saddleback-like) was showed on ECG data of proband, other ECG results of 3 family members showed type 3 Brugada ECG pattern and elevated J-wave respectively. The result of linkage analysis showed the SCN5A gene could be the most possible candidate gene. Direct DNA sequencing revealed a“double peak”in the second nucleotide of codon 1001 in SCN5A gene of proband, which was identified to be a missense mutation (T3002A) after matching and searching in databases. The T→A replacement at the 3002 site of cDNA of SCN5A causing the substitution of leucine by glutamine(L1001P) in the P-loop of the pore-lining region between transmembrane segments S5-S6 of domain DII, which is one of key structures of Nav1.5 cardiac sodium channelα-subunit. This mutation were found in proband, 3 siblings of proband, the daughter of proband, the restriction enzyme digest analysis of other family members and 50 healthy individuals revealed no same mutation in normals were detected. 3 Single Nucleotide Polymorphisms were detected in family members with mutation at the same time.
Conclusions: A novel mutation T3002A of SCN5A was detected in a Chinese Family with Brugada-like electrocardiogram pattern. 5 members of the family were comfirmed with this heterozygous mutation. The results of linkage analysis, direct sequencing and the restriction enzyme digest analysis unanimously support the characteristic of Brugada syndrome as an autosomal dominant inheritance. No history of syncope; nocturnal agonal respiration; ventricular fibrillation; polymorphic ventricular tachycardia; a family history of sudden death under 45 years old were recorded among family members, the only clinical evidence were atypical Brugada-like electrocardiogram pattern records of proband and her 3 siblings and her daughter. However, when undertook genetic detection, all the 5 family members mention above showed an heterozygous mutation T3002A in the second nucleotide of codon 1001 in SCN5A gene, which suggests the likelihood that the defects in sodium channel function repaired by environmental factors. It is also could be the contribution of negative weakening effect that single nucleotide polymorphism brought on the low expression of sodium channel protein caused by mutation. The third explanation is that despite the missense mutation T3002A led the replacement of leucine by glutamine in the P-loop between transmembrane segments S5-S6 of domain DII of protein encoded by SCN5A,the specific extent of the influence on function is unclear, which require the investigation of cell function, such as mutation induction, transfection, patch clamp, action protentials and other research. It’s likely the mutation only partially affected the permeability and selectivity of sodium channel, which means the channel can still maintain its normal physiological function most of the time. This could explain why proband and other family members only have an asymptomatic and atypical Brugada-like electrocardiogram pattern.
引文
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[1] Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol, 2001, 12:268–272.
[2] London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation, 2007, 116:2260–2268.
[3] Weiss R, Barmada MM, Nguyen T, et al. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation, 2002, 105:707–713.
[4] Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation, 2007, 115:442–449.
[5] Van PF, Clark KA, Chatelain FC, et al. Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature, 2004, 429:671–675.
[6] Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channelβ1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest, 2008, 118:2260–2268.
[7] Abbott GW, Butler MH, Bendahhou S, et al. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell, 2001, 104:217–231.
[8] Delpon E, Cordeiro JM, Nunez L, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol, 2008, 1:209–218.
[9] Hu D, Martinez HB, Burashnikov E, et al. A mutation in theβ3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ Cardiovasc Genet (in press), 2009.
[10] Ueda K, Hirano Y, Higashiuesato Y, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet, 2009, 54: 115-121.