营养代谢疾病

20051105 中国人低血钾性周期性麻痹家系:SCN4A新突变位点/王卫庆…//中华内分泌代谢杂志.-2004,20(6).-523～526 运用PCR扩增及反应产物直接测序的方法,对一个中国人低钾周期性麻痹家系32名成员进行基因筛查,并运用亚克隆方法进行证实。结果发现在编码Na通道的基因SCN4A上第2014位核苷酸存在一个新点突变(CGT-     

家族性低钾性周期性麻痹一家系分析

家族性低钾性周期性麻痹临床罕见, 报告1个低钾性周期性麻痹家系, 该家系患病成员均为男性, 主要表现为肢体乏力, 反复低血钾, 但发病频率、起病年龄和严重程度有所不同, 基因检测提示SCN4A基因变异(突变位点R669H)。该位点突变在国内所报道的家系中未见报道。通过该家系分析, 以提高临床医生对该病的认识。     

低钾性周期性麻痹的分子生物学基础

低钾性周期性麻痹是一种与遗传有关的离子通道疾病，目前所知的突变分别是L型电压门控Ca^2 通道编码基因(C4CNIS)Arg528His、Arg1086Cys、Arg1239G1y、Arg1239His、电压门控Na’通道编码基因(SCN4A)Arg669His、Arg672G1y、Arg672His、Arg672Ser、Arg672Cys、Pro1158Ser及电压门控K^ 通道编码基因(KCAE3)Arg83His。不同的突变类型具有不同的临床特点，CACNAIS Arg528His和CAC-NAIS Arg1239His突变者发病较早；SCN4A Arg672Gly突变者发病更早，在女性中表现为不完全外显，发作后肌痛重，病理表现为管性聚集，乙酰唑胺治疗会致肌无力的加重。突变引起的氨基酸改变影响了通道电压感受器的功能，产生异常的静息膜电位，引起兴奋收缩偶联的改变从而导致肌无力的发生。     

低钾性周期性麻痹的分子生物学基础

低钾性周期性麻痹是一种与遗传有关的离子通道疾病,目前所知的突变分别是L型电压门控Ca2+通道编码基因(CACNAlS)Arg528His、Arg1086Cys、Arg1239Gly、Arg1239His、电压门控Na+通道编码基因(SCN4A)Arg669His、Arg672Gly、Arg672His、Arg672Ser、Arg672Cys、Pro1158Ser及电压门控K+通道编码基因(KCNE3)Arg83His.不同的突变类型具有不同的临床特点,CACNAlS Arg528His和CACNAIS Arg1239His突变者发病较早;SCN4A Arg672Gly突变者发病更早,在女性中表现为不完全外显,发作后肌痛重,病理表现为管性聚集,乙酰唑胺治疗会致肌无力的加重.突变引起的氨基酸改变影响了通道电压感受器的功能,产生异常的静息膜电位,引起兴奋收缩偶联的改变从而导致肌无力的发生.     

遗传性长QT综合征SCN5A基因delD1790新突变

目的研究中国人遗传性长QT综合征3型(LQT3)相关基因SCN5A突变情况。方法以KCNQ1和KC-NH2基因筛查无突变,心电图表现符合LQT3的3例LQTS患者为研究对象,聚合酶链反应和双脱氧末端终止测序法对所有患者进行SCN5A基因扫描,对阳性结果者进行家系中其他成员的筛查。结果在1个LQTS家系发现SCN5A基因突变。该家系先证者及其母亲SCN5A基因第28外显子上存在一个杂合突变,即在5368-5370位存在3碱基(GAC)缺失,导致1790位密码子天冬氨酸(Asp)缺失(delD1790)。结论在1个中国LQTS家系发现了一个LQT3相关的SCN5A基因新突变(delD1790)。     

中国汉族人Brugada综合征患者SON5A基因Ⅳ区一个新的突变

背景 Brugada综合征是一种易导致猝死的具有遗传倾向的疾病,与编码心肌钠通道的基因突变有关.目的 研究中国Brugada综合征患者SCN5A基因的碱基改变情况.方法 对15例先证者及家系进行直接SCN5A基因测序.DNA来源于患者外周血白细胞.全部28个外显子通过设计的40对引物进行PCR扩增,扩增后的产物直接测序.结果 在一个家系上发现了一个错义突变,即G5080A(R1628Q),该突变导致心肌细胞钠通道的α亚基第Ⅳ结构域的第4片段发生改变.在150个正常对照者未发现此碱基改变.结论 G5080A(R1628Q)可能是中国Brugada综合征患者SCN5A基因新的突变位点.     

中国汉族人Brugada综合征患者SCN5A基因Ⅳ区一个新的突变

背景 Brugada 综合征是一种易导致猝死的具有遗传倾向的疾病,与编码心肌钠通道的基因突变有关。目的研究中国 Brulgada 综合征患者 SCN5A 基因的碱基改变情况。方法对15例先证者及家系进行直接SCN5A 基因测序。DNA 来源于患者外周血白细胞。全部28个外显子通过设计的40对引物进行 PCR 扩增,扩增后的产物直接测序。结果在一个家系上发现了一个错义突变,即 G5080A(R1628Q),该突变导致心肌细胞钠通道的α亚基第Ⅳ结构域的第4片段发生改变。在150个正常对照者未发现此碱基改变。结论 G5080A(R1628Q)可能是中国 Brugada 综合征患者 SCN5A 基因新的突变位点。     

一个中国大家系Brugada综合征相关基因SCN5A的突变位点检测

目的：研究一个中国大家系Brugada综合征相关基因SCN5A的突变情况。方法：收集一个Brugada家系（43例）的临床资料,采用聚合酶链反应及直接测序法对此家系进行SCN5A基因突变检测,同时对136名家系外健康对照者的该位点进行单链构象多态性（SSCP）分析。结果：在Brugada家系中发现了一个杂合变异,即SCN5A基因第12外显子上发现一个错义变异（A1685G）,导致代表组氨酸的558位密码子突变为精氨酸（H558R）。结论：在中国人Brugada综合征患者的SCN5A基因上发现了一个已经报道的错义多态位点（H558R）。     

新疆两例尼曼-皮克病家系分析

目的对2例老年C型尼曼-皮克病(Niemann-Pick disease type C,NPC)患者及家系的NPC1和NPC2基因进行测序,分析基因型与表型关系。方法采集2例NPC患者及家系外周血,提取基因组DNA,进行引物设计扩增,直接基因测序检测。结果2例患者在NPC1基因6号外显子发现1个杂合子位点A644G(H215R),导致第215位氨基酸由His突变为Arg;18号外显子发现1个杂合子位点N931N(C2793T),氨基酸编码没有改变;2例家系其他成员未发现异常。结论 NPC患者具有典型NPC临床特征,在基因水平上发现,相关基因突变位点或新的突变位点,但家系基因特征不明显。因此,对于老年NPC患者或存在其他致病因素。     

中国汉族人Brugada综合征患者SCN5A基因Ⅳ区一个新的突变

背景Brugada综合征是一种易导致猝死的具有遗传倾向的疾病，与编码心肌钠通道的基因突变有关。目的研究中国Brugada综合征患者SCN5A基因的碱基改变情况。方法对15例先证者及家系进行直接SCN5A基因测序。DNA来源于患者外周血白细胞。全部28个外显子通过设计的40对引物进行PCR扩增，扩增后的产物直接测序。结果在一个家系上发现了一个错义突变，即G5080A（R1628Q），该突变导致心肌细胞钠通道的α亚基第IV结构域的第4片段发生改变。在150个正常对照者未发现此碱基改变。结论G5080A（R1628Q）可能是中国Brugada综合征患者SCN5A基因新的突变位点。     

Brugada综合征一家系中2例患者的SCN5A基因突变及意义

目的 观察Brugada综合征一家系中2例患者的SCN5A基因突变情况,并探讨其意义.方法 选择Brugada综合征一家系2例患者,采用直接测序法对其SCN5A基因突变进行检测.结果 该家系中发现1个纯合变异,即SCN5A基因第28外显子上的同义变异（C5457T）,其所编码的1819位天冬氨酸密码子没有发生改变.结论 该Brugada综合征家系2例患者的SCN5A基因上存在1个同义变异,但SCN5A基因不是患者的致病基因.     

一个扩张型心肌病伴房室传导阻滞家系SCN5A基因的突变研究

目的研究一个扩张型心肌病伴房室传导阻滞家系中心脏钠离子通道基因（voltagegated sodium channel type V,SCN5A）的遗传突变或多态位点。方法应用聚合酶链反应结合DNA直接测序技术对该家系的23位直系成员进行SCN5A基因编码区全部28个外显子的检测;对于新发现的变异位点筛查133名无血缘关系的正常人作为对照。结果在该家系中共检测到4个遗传变异,分别为c．87G〉A（A29A）,C．731T〉C（1244T）,C．3578G〉A（R1193Q）和c．5457T〉C（D1819D．）。其中c．731T〉C（1244T）为新发现的遗传变异,位于第7外显子,碱基的变异导致氨基酸第244位由苏氨酸代替异亮氨酸。家系中有4名成员携带1244T,但是133名健康对照者中未发现该变异。结论在一个扩张型心肌病伴房室传导阻滞家系中发现了SCN5A基因的新遗传变异。     

The occurrence of Brugada syndrome and isolated cardiac conductive disease in the same family could be due to a single SCN5A mutation or to the accidental association of both diseases.

AIMS: The distinct cardiac arrhythmia diseases, Brugada syndrome (BS) and isolated cardiac conduction disease (ICCD) are caused by heterozygous mutations in the SCN5A gene. Previous studies have demonstrated an intriguing association between ICCD and BS with the same mutation in the SCN5A gene. METHODS AND RESULTS: The proband of a multigenerational family presented BS and a familial history of sudden death. We performed clinical evaluations in family members including drug testing and screening for SCN5A mutations. Based on electrocardiogram features, we identified four individuals with BS, two with ICCD and one compatible with both. For five individuals, one with BS and ICCD, three with BS and one with ICCD, we characterized a heterozygous C- to T- mutation at position 4313 (P1438L) in the SCN5A gene. Expression studies of the P1438L mutation showed non-functional channels. The proband's father with the BS phenotype was not a carrier of the new SCN5A mutation. CONCLUSION: We report the case of a family with BS and/or ICCD and describe a novel mutation, the P1438L SCN5A mutation. In this family, the occurrence of BS and ICCD could be due to this single mutation but also to the accidental association of both diseases.     

Brugada综合征SCN5A基因的三个新突变

目的 研究Brugada综合征相关基因SCN5A突变情况。方法 以4例Brugada综合征患者和9例临床可疑Brugada综合征患者为研究对象,采用聚合酶链反应和双脱氧末端终止测序法对所有患者进行SCNSA基因扫描。对阳性结果者进行家系中其他成员的筛查。结果 在1个Brugada综合征家系发现两个杂合突变,即SCN5A基因第3外显子上发现一错义突变（G283A）,导致代表缬氨酸残基的第95位密码子突变为异亮氨酸残基（V95I）,第28外显子上也发现一错义突变（CA946T）,导致代表丙氨酸的第1649位密码子突变为缬氨酸（A1649V）。在1个临床可疑Brugada综合征家系发现一杂合突变,即SCN5A基因第28外显子缺失3个碱基（TCT）,导致代表苯丙氨酸残基的第1617位密码子缺失（delF1617）。结论 在Brugada综合征患者发现了3个SCN5A基因新突变（V95I、A1649V、delF1617）。     

Investigation of APCMutations in a Turkish Familial Adenomatous Polyposis Family by Heterodublex Analysis

PURPOSE Familial adenomatous polyposis is an autosomal dominant disease characterized by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis coli gene are primarily responsible for the development of this disease. This study was designed to investigation of adenomatous polyposis coli (APC) gene mutations in members of familial adenomatous polyposis family to identify individuals at risk of the disease.METHODS We examined one patient with familial adenomatous polyposis and 21 family members including one affected person from familial adenomatous polyposis and 20 nonsymptomatic persons. We studied E, D, F, and G segments of exon 15 of the adenomatous polyposis coli gene by heteroduplex analysis.RESULTS We used silver staining method for staining. We found a mutation for five persons at segment F of exon 15 of the adenomatous polyposis coli gene. Two of them were affected by colorectal cancer, one of whom was the proband, and the other three were nonsymptomatic family members. The pathogenetic mutation was a T deletion at codon 1172, causing a frameshift in the adenomatous polyposis coli gene, as a result of the sequencing analysis of these cases.CONCLUSIONS Investigation of adenomatous polyposis coli gene mutations is very important for the identification of genetic susceptibility to colorectal cancer and for the definition of tumor developing at an early stage. Furthermore, the identification of this mutation for the first time in a Turkish family will be useful to foster further studies on familial adenomatous polyposis in Turkey.     

Thr1313Met mutation in skeletal muscle sodium channels in a Japanese family with paramyotonia congenita

A 37-year-old Japanese woman was referred from another clinic to confirm the diagnosis of myotonia congenita. She had experienced cold-induced myotonia and muscle stiffness from early childhood. Of her three children, her elder son and her daughter have clinical features similar to hers. They experience neither grip nor percussion myotonia during warm weather, whereas myotonia is provoked by cold. Her younger son has no symptoms. DNA analyses of the SCN4A gene showed a C to T transition at nucleotide position 3938 in exon 22 of SCN4A (Thr1313Met) in all three affected family members, but not in the unaffected son. Paramyotonia congenita, the prevalence of which is very low in Japan, was diagnosed based on their clinical features and DNA analysis results.     

中国一家系Brugada综合征相关基因SCN5A突变位点的检测

目的研究一个中国家系Brugada综合征相关基因SCNSA的突变情况。方法收集一个Brugada家系的临床资料,采用聚合酶链反应及直接测序法对该家系进行SCN5A基因突变检测,同时对136例家系外健康对照者的该位点进行单链构象多态性分析。结果在Brugada家系中发现了两个杂合变异,即SCN5A基因第二外显子上发现一个同义变异（A129G）,没有导致氨基酸的改变（A29A）;第26外显子发现一个错义变异（T4492A）,导致代表酪氨酸的1494位密码子突变为天门冬酰胺（Y1494N）。结论在中国人Brugada综合征患者的SCNSA基因上发现了一个已经报道的同义多态位点（A29A）及一个新的错义突变位点（Y1494N）。     

A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill

Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G). Eight relatives were homozygous for both polymorphisms, which occurred in only approximately 7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS.     

MYBPC3基因G12101A和MYH7基因G15391A突变与肥厚型心肌病临床表型

目的 研究中国人家族性肥厚型心肌病(HCM)的致病基因突变位点,分析基因型与临床表型的相互关系.方法 在2个中国汉族HCM家系中进行心脏肌钙蛋白T基因(TNNT2)、心脏肌球蛋白结合蛋白C基因(MYBPC3)和心脏β-肌球蛋白重链基因(MYH7)的突变筛查,聚合酶链式反应(PCR)扩增基因功能区外显子片段并对PCR产物进行测序分析.结果 在ZZJ家系接受调查的8名成员中有4名成员携带MYBPC3基因G12101A杂合突变,该突变位点位于MYBPC3基因的21号外显子并使668位的精氨酸(R)转换为组氨酸(H),携带该突变的家族成员发病年龄较晚且均无梗阻及晕厥史.在FHL家系接受调查的6名成员中有3名成员携带MYH7基因G15391A杂合突变,该突变位点位于MYH7基因的23号外显子并使930位的谷氨酸(E)转换为赖氨酸(K),该突变导致的临床表型呈现发病年龄早、梗阻率高以及外显率高的特点.两家系成员TNNT2基因未发现突变,且正常对照组相同位置未发现异常.结论 MYBPC3基凶和MYH7基因是我国家族性HCM的致病基因,MYBPC3基因G12101A突变所致HCM临床症状相对较轻,而MYH7基因G15391A突变所致HCM临床症状出现早、进展较快且预后较差,是一种恶性突变.     

SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias

INTRODUCTION: We aimed at identifying the molecular defect underlying the clinical phenotype of a Finnish family with a cardiac conduction defect and atrial arrhythmias. METHODS AND RESULTS: A large Finnish family was clinically evaluated (ECG, 24-hour ambulatory ECG, echocardiography). We performed linkage analysis with markers flanking the SCN5A gene and subsequently sequenced the SCN5A gene. Five family members had atrial arrhythmias and intracardiac conduction defects, and due to bradycardia needed a pacemaker when adolescents. No heart failure or sudden cardiac death was observed. Left ventricle dilatation was seen in one individual and three individuals had a slightly enlarged right ventricle. Premature death due to stroke occurred in one subject during the study, and two other members had suffered from stroke at young age. Linkage analysis favored the role of the SCN5A gene in disease pathogenesis, and direct sequencing disclosed D1275N mutation. This alteration was present not only in all six affected individuals, but also in two young individuals lacking clinical symptoms. CONCLUSIONS: Cardiac conduction defect and atrial arrhythmias in a large Finnish family appear to result from the SCN5A D1275N mutation. Although no sudden cardiac death was recorded in the family, at least three affected members had encountered brain infarction at the age of 30 or younger.