周期性麻痹的临床及相关基因突变研究
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摘要
研究背景 周期性麻痹(periodic paralysis，PP)作为典型离子通道病的代表，是一大组以发作性肌无力伴随血钾浓度变化为主要临床特征的疾患。此病多见于儿童和年轻人，严重者可因呼吸肌麻痹或心律失常危及生命。该病病因及发病机制一直不详，治疗手段以对症为主，尚无有效的预防方法。目前国内外在周期性麻痹及其相应离子通道研究上存在的问题如下：①低钾型周期性麻痹(hypokalemic periodic paralysis，hypoKPP)可能与钙通道CACNA1S基因、钠通道SCN4A基因甚至钾通道KCNE-3基因缺陷有关。这些通道功能异常如何引起肌膜异常去极化过程、以及降低细胞外钾离子浓度的机制尚不十分清楚。②高钾型周期性麻痹(hyperkalemic periodic paralysis，hyperKPP)与SCN4A基因突变有关。但是，突变SCN4A基因影响膜电位的详细机制仍不十分清楚。③正常血钾型周期性麻痹(normokalemic periodicparalysis，normoKPP)国内外研究甚少。其是否为独立疾病，发病机制以及其与hyperKPP的关系尚不清楚。④国内尚缺乏周期性麻痹的离子通道基因研究，国人各型周期性麻痹的致病基因及基因突变方式不清。我们此研究的目的是探讨国人各型周期性麻痹的临床特征及相关基因突变特点。本研究分为三个部分：
一、各型周期性麻痹家系资源的收集和保存及相关基因突变筛查程序的建立
本研究的目的是建立一个包括临床资料、家系资料及血样和DNA样品的各型周期性麻痹遗传资源库。在本研究中我们首先建立了遗传性周期性麻痹的遗传资源收集网络，通过网络获得信息，经临床筛查明确诊断后，根据
解放军总医院‘军医进修学院博士论文
摘要
知情同意的原则采集临床资料及血样。我们利用此网络系统收集到来自n
个家系的25例normoKPP患者(包括有家族史的3个家系和8例散发病例)，
1个家系的7例hyPerKPP患者及34例hypoKPP患者(6例有家族史，28例
为散发病例)。这些宝贵的遗传资源是进行周期性麻痹基因研究的基础。
鉴于与三型周期性麻痹相关的离子通道基因SCN4A基因及CACNAIS
基因已经被克隆，并且外显子与内含子的分界点己经界定，我们利用美国
National Center for Bioteehnology hiformation的网站
http://w叭八刀.nchi.nlm.nih.gov/获得二基因的外显子核昔酸序列，并设计引物进
行PCR扩增，单链核营酸构象多态性分析(single strand conformation
polimophism，sSCp)或者变性液相色谱(denatUring high performance liquld
chromatography，DHPLC)技术检测。如果目标产物出现异常条带或洗脱峰
提示存在匹配的异源双链，且与正常对照不同，行序列分析。明确突变碱基
后，在h林p刃叭八叨w.ncbi.nlm.nih.gov儿fast检测是否发生氨基酸序列改变并定
位。结果显示发现多处杂合多态位点，提示本实验设计对中国人三型周期性
麻痹的SCN4A基因及CACNAls基因进行研究是行之有效的。
二、高钾型及正常血钾型周期性麻痹的SCN4A基因突变研究
(一)家族性高钾型周期性麻痹的SCN4A基因突变研究
本研究目的是为了明确hyperK卫P与SCN4A基因的关系。我们有幸获得
了一个5代遗传32名家族成员中14名患病的hyperKPP家系，我们收集了
该家系的7例患者的临床资料和血样，应用DHPLC技术筛查SCN4A基因全
部24个外显子，对发现异常洗脱峰者进行连锁分析并进行测序。结果显示该
家系具有典型的h冲erKpp临床特征，无肌强直表现及早显、性别偏移现象，
解放军总医院.军医进修学院博士论文
摘要
病程呈良性过程，发病早晚与症状严重程度及预后无相关。DHPLC筛查先证
者SCN4A基因，发现在外显子13、23及24存在杂合二倍体。测序及连锁
分析证实位于外显子13的碱基替换引起氨基酸序列改变，为Thr704Met;23
的碱基替换虽引起氨基酸序列改变并与疾病连锁，而进一步研究显示该突变
为一良性多态;外显子24的碱基替换为同义突变。结论为该hyPerKPP家系
与SCN4A基因相关，并发生最常见的突变Thr704Met。
(二)DHPLC筛查正常血钾型周期性麻痹患者SCN4A基因突变
此部分目的是探讨正常血钾型周期性麻痹(normoKPP)在中国人群的临
床特点并在基因水平上研究norm。即P与高钾型周期性麻痹(hyperKpp)的
关系。我们收集了11个normoKPP家系25例患者的临床资料并保存血样，
提取外周血基因组DNA，PCR一DHPLC检测normoKPP患者SCN4A基因24
个外显子，对发现有异常洗脱峰的PCR产物进行测序，并进行基因定位。结
果显示家系5先证者发作期CK轻度升高，余常规实验室检查均正常，肌电
图正常。家系4的患儿在发作间期行肌肉活检，光镜下未见异常，电镜下示
局灶性肌纤维变性。基因研究发现在11个normoKI，P家系中，①1家系中14
例患者具有一致的异常洗脱峰，测序证实为Met1592Val突变。②2例散发病
例发生、恤】781ne替换，并证实该突变为SCN4A基因mRNA上唯一错义突变。
③1家系和1散发病例发现新突变Arg675Gln，可能与疾病相关。④其余家庭
的 SCN4A基因全部24个外显子未发现有意突变。因此我们认为国人
normoKPP患者存在Val78llle、Metl592Val、A堪675Gln等突变;Met1592Val
可导致normoKPP，发现的新突变Arg675Gin可能导致norm。口P;至少部分
Background As one form of ion channelopathies, periodic paralyses (PP) are a group of autosomal dominant familial disorders involving the abnormal function of ion channels and they are characterized by paralysis attacks of varying severity, accompanied by a change in blood potassium levels. The diseases may have their onset at any time from infancy or childhood to the third decades of life. During attacks, muscles of the lower extremities are initially affected, followed by the lower trunk and arms, and even dyspnea or cardiac arrhythmia. The etiology and nosogenesis of the diseases are not clear enough to have a very effective therapeutic tool or preventive measure. The progresses in molecular biology on three types of periodic paralyses are as follows: (1) Hypokalemic periodic paralysis(hypoKPP) is mainly related to the mutation in the muscle dihydropyridine-sensitive calcium channel a l-subunit(CACNAlS), and less the muscle sordium channel a 1-subunit (SCN4A), but the mechanisms of hypokalemia are yet not
clear, (2)hyperkalemic periodic paralysis (hyperKPP) is caused by the missense mutation of SCN4A gene, but the detailed mechanisms of the mutation influencing membrane potential are not very clear. (3)The genetic researches on normokalemic periodic paralysis (normoKPP) are very few, and the relationship between normoKPP and hyperKPP is still in doubts. (4) In China, the genetic researches on three types of periodic paralyses are still in
absence, and the mode of gene mutation with Chinese PP patients is not clear. In this research we aim to clarify the clinical and genetic features of three types of PP with Chinese patients. This research is devided into three parts. PART ONE: Collecting and characterizing the genetic resources for periodic paralyses, and establishing the process of scanning SCN4A gene and CACNA1S gene for disease-related mutation
The objective of this study was to establish a repository for blood DNA samples accompanied with clinical and pedigree data. In this study, we firstly established a network for collecting genetic resources of three types of PP in China. With this network, we collected 25 normoKPP patients in 11 unrelated families in which three were with family history, and eight were scattered cases, seven patients in one hyperKPP family, and 34 hypoKPP patients in which six were with family history, and 28 were scattered cases. All these invaluable resources were important for the genetic researches on periodic paralyses.
Secondly, we designed primers for all 24 exons of SCN4A gene, and exon 11 and exon 30 of CACNA1S gene with the help of the website http://www.ncbi.nlm.nih.gov/ of National Center for Biotechnology in USA. Then, the PCR products were checked with single strand conformation polymorphism (SSCP) or with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal conformer or elution peak. Those discovered mutations were checked and located with the help from the website http://www.ncbi.nlm.nih.gov/. The results showed that we found some Heterozygotes, which means our design for the genetic researches on periodic paralyses with Chinese patients is available.
PART TWO: Scanning SCN4A gene for mutations in Chinese families with hyperkalemic periodic paralysis or normokalemic periodic paralysis
(1) Screening SCN4A gene for mutations in a Chinese family with hyperkalemic periodic paralysis
In this part, we aim to study the clinical features of hyperkalemic periodic paralysis (hyperKPP) and to confirm the relationship between SCN4A gene and hyperKPP with Chinese patients. The clinical features of 7 patients in a Chinese family with hyperKPP were summarized. All 24 exons of SCN4A gene were screened with DHPLC technology, and then sequence analysis was performed on those with abnormal elution peak. The Results were as follows: This family showed typical clinical features of hyperKPP without myotonia or paramyotonia. The progress of most patients was benign. Two mutations were foun
一、各型周期性麻痹家系资源的收集和保存及相关基因突变筛查程序的建立
本研究的目的是建立一个包括临床资料、家系资料及血样和DNA样品的各型周期性麻痹遗传资源库。在本研究中我们首先建立了遗传性周期性麻痹的遗传资源收集网络，通过网络获得信息，经临床筛查明确诊断后，根据
解放军总医院‘军医进修学院博士论文
摘要
知情同意的原则采集临床资料及血样。我们利用此网络系统收集到来自n
个家系的25例normoKPP患者(包括有家族史的3个家系和8例散发病例)，
1个家系的7例hyPerKPP患者及34例hypoKPP患者(6例有家族史，28例
为散发病例)。这些宝贵的遗传资源是进行周期性麻痹基因研究的基础。
鉴于与三型周期性麻痹相关的离子通道基因SCN4A基因及CACNAIS
基因已经被克隆，并且外显子与内含子的分界点己经界定，我们利用美国
National Center for Bioteehnology hiformation的网站
http://w叭八刀.nchi.nlm.nih.gov/获得二基因的外显子核昔酸序列，并设计引物进
行PCR扩增，单链核营酸构象多态性分析(single strand conformation
polimophism，sSCp)或者变性液相色谱(denatUring high performance liquld
chromatography，DHPLC)技术检测。如果目标产物出现异常条带或洗脱峰
提示存在匹配的异源双链，且与正常对照不同，行序列分析。明确突变碱基
后，在h林p刃叭八叨w.ncbi.nlm.nih.gov儿fast检测是否发生氨基酸序列改变并定
位。结果显示发现多处杂合多态位点，提示本实验设计对中国人三型周期性
麻痹的SCN4A基因及CACNAls基因进行研究是行之有效的。
二、高钾型及正常血钾型周期性麻痹的SCN4A基因突变研究
(一)家族性高钾型周期性麻痹的SCN4A基因突变研究
本研究目的是为了明确hyperK卫P与SCN4A基因的关系。我们有幸获得
了一个5代遗传32名家族成员中14名患病的hyperKPP家系，我们收集了
该家系的7例患者的临床资料和血样，应用DHPLC技术筛查SCN4A基因全
部24个外显子，对发现异常洗脱峰者进行连锁分析并进行测序。结果显示该
家系具有典型的h冲erKpp临床特征，无肌强直表现及早显、性别偏移现象，
解放军总医院.军医进修学院博士论文
摘要
病程呈良性过程，发病早晚与症状严重程度及预后无相关。DHPLC筛查先证
者SCN4A基因，发现在外显子13、23及24存在杂合二倍体。测序及连锁
分析证实位于外显子13的碱基替换引起氨基酸序列改变，为Thr704Met;23
的碱基替换虽引起氨基酸序列改变并与疾病连锁，而进一步研究显示该突变
为一良性多态;外显子24的碱基替换为同义突变。结论为该hyPerKPP家系
与SCN4A基因相关，并发生最常见的突变Thr704Met。
(二)DHPLC筛查正常血钾型周期性麻痹患者SCN4A基因突变
此部分目的是探讨正常血钾型周期性麻痹(normoKPP)在中国人群的临
床特点并在基因水平上研究norm。即P与高钾型周期性麻痹(hyperKpp)的
关系。我们收集了11个normoKPP家系25例患者的临床资料并保存血样，
提取外周血基因组DNA，PCR一DHPLC检测normoKPP患者SCN4A基因24
个外显子，对发现有异常洗脱峰的PCR产物进行测序，并进行基因定位。结
果显示家系5先证者发作期CK轻度升高，余常规实验室检查均正常，肌电
图正常。家系4的患儿在发作间期行肌肉活检，光镜下未见异常，电镜下示
局灶性肌纤维变性。基因研究发现在11个normoKI，P家系中，①1家系中14
例患者具有一致的异常洗脱峰，测序证实为Met1592Val突变。②2例散发病
例发生、恤】781ne替换，并证实该突变为SCN4A基因mRNA上唯一错义突变。
③1家系和1散发病例发现新突变Arg675Gln，可能与疾病相关。④其余家庭
的 SCN4A基因全部24个外显子未发现有意突变。因此我们认为国人
normoKPP患者存在Val78llle、Metl592Val、A堪675Gln等突变;Met1592Val
可导致normoKPP，发现的新突变Arg675Gin可能导致norm。口P;至少部分
Background As one form of ion channelopathies, periodic paralyses (PP) are a group of autosomal dominant familial disorders involving the abnormal function of ion channels and they are characterized by paralysis attacks of varying severity, accompanied by a change in blood potassium levels. The diseases may have their onset at any time from infancy or childhood to the third decades of life. During attacks, muscles of the lower extremities are initially affected, followed by the lower trunk and arms, and even dyspnea or cardiac arrhythmia. The etiology and nosogenesis of the diseases are not clear enough to have a very effective therapeutic tool or preventive measure. The progresses in molecular biology on three types of periodic paralyses are as follows: (1) Hypokalemic periodic paralysis(hypoKPP) is mainly related to the mutation in the muscle dihydropyridine-sensitive calcium channel a l-subunit(CACNAlS), and less the muscle sordium channel a 1-subunit (SCN4A), but the mechanisms of hypokalemia are yet not
clear, (2)hyperkalemic periodic paralysis (hyperKPP) is caused by the missense mutation of SCN4A gene, but the detailed mechanisms of the mutation influencing membrane potential are not very clear. (3)The genetic researches on normokalemic periodic paralysis (normoKPP) are very few, and the relationship between normoKPP and hyperKPP is still in doubts. (4) In China, the genetic researches on three types of periodic paralyses are still in
absence, and the mode of gene mutation with Chinese PP patients is not clear. In this research we aim to clarify the clinical and genetic features of three types of PP with Chinese patients. This research is devided into three parts. PART ONE: Collecting and characterizing the genetic resources for periodic paralyses, and establishing the process of scanning SCN4A gene and CACNA1S gene for disease-related mutation
The objective of this study was to establish a repository for blood DNA samples accompanied with clinical and pedigree data. In this study, we firstly established a network for collecting genetic resources of three types of PP in China. With this network, we collected 25 normoKPP patients in 11 unrelated families in which three were with family history, and eight were scattered cases, seven patients in one hyperKPP family, and 34 hypoKPP patients in which six were with family history, and 28 were scattered cases. All these invaluable resources were important for the genetic researches on periodic paralyses.
Secondly, we designed primers for all 24 exons of SCN4A gene, and exon 11 and exon 30 of CACNA1S gene with the help of the website http://www.ncbi.nlm.nih.gov/ of National Center for Biotechnology in USA. Then, the PCR products were checked with single strand conformation polymorphism (SSCP) or with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal conformer or elution peak. Those discovered mutations were checked and located with the help from the website http://www.ncbi.nlm.nih.gov/. The results showed that we found some Heterozygotes, which means our design for the genetic researches on periodic paralyses with Chinese patients is available.
PART TWO: Scanning SCN4A gene for mutations in Chinese families with hyperkalemic periodic paralysis or normokalemic periodic paralysis
(1) Screening SCN4A gene for mutations in a Chinese family with hyperkalemic periodic paralysis
In this part, we aim to study the clinical features of hyperkalemic periodic paralysis (hyperKPP) and to confirm the relationship between SCN4A gene and hyperKPP with Chinese patients. The clinical features of 7 patients in a Chinese family with hyperKPP were summarized. All 24 exons of SCN4A gene were screened with DHPLC technology, and then sequence analysis was performed on those with abnormal elution peak. The Results were as follows: This family showed typical clinical features of hyperKPP without myotonia or paramyotonia. The progress of most patients was benign. Two mutations were foun
引文
1. Chesson AL Jr, Schochet SS Jr, Peters BH. Biphasic periodic paralysis. Arch Neurol 36, Nov 1979: 700-704
2. Pearson CM. The periodic paralyses: differetial feature and pathological observations in permanent myopathic weakness. Brain 1964; 87: 341-353
3. Brooke MH. A clinician's view of neuromuscular disease. Baltimore, Williams & Wilkins CO, 1977, pp 182-194
4. Cannon SC. An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord 2002; 12(6): 533-43
5. Kuzmenkin A, Muncan V, Jurkat R K, et al. Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type Ⅱ. Brain. 2002; 125(Pt 4): 835-43.
6. Bendahhou S, Cummins TR, Tawil R, et al. Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation. J Neuroscience 1999; 19: 4762-71
7. Panas M, Kalfakis N, Karadimas C, et al. Episodes of generalized weakness in two sibs with. the C164T mutation of the connexin 32 gene. Neurology. 2001, 27: 1906-8
8. Bendahhou S, Cummins TR, Griggs RC, et al. Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol. 2001; 50(3): 417-20
9. Lehmann H F, Jurkat R K, Rudel R. Periodic paralysis: understanding channelopathies. Curt Neurol Neurosci Rep 2002; 2(1): 61-69
10. Celesia GG. Disorders of membrane channels or channelopathies. Clin Neurophysiol 2001; 112(1): 2-18
11. Felix R. Channelopathies: ion channel defects linked to heritable clinical disorders. J Med Genet 2000; 37(10): 729-40
12. Pulst SM. Genetic linkage analysis. Arch Neurol 1999; 56(6): 667-72
13. Cooper EC, Jan LY. Ion channel genes and human neurological disease: recent progress, prospects, and challenges. Proc Natl Acad Sci USA 1999; 96: 4759-66
14. Hayward LJ, Sandoval GM, Cannon SC. Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 1999, 52: 1447-53
15. Chinnery PF, Walls TJ, Hanna MG, et al. Normokalemic periodic paralysis revisited: Does it exist? Ann Neurol 2002 Aug; 52(2): 251-252
16. Eduardo M, Toshio Y, Gordon FT. Topical review: structure and function of voltage-gated sodium channel. J Physiol, 1998, 508: 647-657
17. Rohl CA, Boeckman, TA, Baker C, et al. Solution structure of the sodium channel inactivation gate. Biochemistry, 1999, 38, 855-861
18. Isom LL, De Jough KS, Patton DE, et al. Primary structure and functional expression of the β1 subunit of the rat brain sodium channel. Science, 1992, 256, 839-842
19. Isom LL, Ragsdale DS, De Jough KS, et al. Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM-motif. Cell, 1995, 83, 433-442
20. William AC. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron, 2000, 26: 13-25
21. Lehmann-Horn F, G Kuther, K Ricker, et al. Adynamia episodica hereditaria
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22. Lehmann-Horn F, R Rudel, K Ricker. Memberane defects in paramyotonia congenita (Eulenburg). Muscle Nerve, 1987, 10: 633-641
23. George AC, GS Iyer, R Kleinfeld, et al. Genomic orgnization of the human skeletal muscle sodium channel gene. Genomics, 1993, 15: 598-606
24. Orita M, Iwahana H, Kanazawa H, et al. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Natl Acad Sci USA, 1989, 86: 2766-2770
25. Gross E, Amord N, Gorttle J, et al. A comparison of BRAC1 mutation analysis by direct sequencing, SSCP, and DHPLC. Hum Genet, 1999, 105: 72-78
26. Hoffman EP. Voltage-gated ion channelopathies: inherited disorders cuased by abnormal sodium, chloride, and calsium regulation in skeletal muscle. Annu Rev Med, 1995, 46: 431-441
27. Catterall WA. Structure and function of voltage-gated ion channels. Annu Rev Biochem, 1995, 64: 394-531
28. Bendahhou S, CumminsTR, Griggs, RC, et al. Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 2001; 50(3): 417-20
29. Steinberg D, Maisonobe T, Jurkat-Rott K, et al. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain. 2001, 124: 1091-9.
30. Caciotti A, MorroneA, Domenici R, et al. Severe prognosis in a large family with hypokalemic periodic paralysis. Muscle-Nerve. 2003; 27(2): 165-9
2. Pearson CM. The periodic paralyses: differetial feature and pathological observations in permanent myopathic weakness. Brain 1964; 87: 341-353
3. Brooke MH. A clinician's view of neuromuscular disease. Baltimore, Williams & Wilkins CO, 1977, pp 182-194
4. Cannon SC. An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul Disord 2002; 12(6): 533-43
5. Kuzmenkin A, Muncan V, Jurkat R K, et al. Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type Ⅱ. Brain. 2002; 125(Pt 4): 835-43.
6. Bendahhou S, Cummins TR, Tawil R, et al. Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation. J Neuroscience 1999; 19: 4762-71
7. Panas M, Kalfakis N, Karadimas C, et al. Episodes of generalized weakness in two sibs with. the C164T mutation of the connexin 32 gene. Neurology. 2001, 27: 1906-8
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