一原发性红斑肢痛症家系的SCN9A基因突变检测与排除定位
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摘要
背景:原发性红斑肢痛症(primary erythermalgia,PETA)是一种罕见的常染色体显性遗传病,主要表现为不同程度的阵发的四肢末端灼痛,伴肢末端皮肤发红,常由运动或温度变化诱发或加重,疾病发作时患肢处于低温环境可使症状缓解或减轻。目前致病机理不清,尚无特效的治疗方法,该病给患者及其家人身心带来严重的伤害。有研究将PETA致病基因定位于2q24.1～24.3,并发现该区间内的SCN9A基因为该病的致病基因。SCN9A基因突变的致病机制正在研究中。亦有研究在一些PETA家系的中未检测到SCN9A外显子突变,提示PETA有遗传异质性,寻找新的PETA致病基因进而研究其致病机制成为目前科研的热点。
目的:求证一湖南PETA家系是否具有新的致病基因,探讨新的致病基因位点是否位于2q24.1～24.3的D2S1353～D2S1776区间。
方法与结果:对一湖南PETA家系进行了调查,收集足够的家系资料,以便进行家系连锁分析得到有意义的LOD值。对该家系先症者进行SCN9A基因全部26个外显子正反向测序,未发现SCN9A异常突变,进而在2q24.1～24.3选取6个微卫星标记(STR),在部分家系成员中作连锁分析,排除该PETA家系致病基因定位于2q24.1～24.3的D2S1353～D2S1776区间。
结论:该湖南PETA家系不存在SCN9A基因外显子突变,提示有新的致病基因,新致病基因位点不在D2S1353～D2S1776区间。
Backgrounds: Primary erythromelalgia (PETA) is a rare disease act as autosomal dominant inheritance, characteristic mainly for the burning sensation of different levels of the end of limbs with the end of limb skin redness, often induced by the movement or temperature changes. Symptoms relief when expose to a low temperature environment such as cool water. The pathogenic mechanism is unclear, and there is no effective cure it by now. PETA bring serious physical and mental harm to patients and their family members. Some studies have mapped its virulence gene to 2q24.1～24.3, and found SCN9A is the virulence gene. The pathogenic mechanisms of SCN9A mutation is under studying. But in some PETA family, SCN9A mutation was not detected, suggesting genetic heterogeneity of PETA. Then searching for a new virulence gene become a research hot.
Obectives: To identify whether the PETA family of HUNAN has new disease gene and whether the gene loci is in 2q24.1～24.3.
Methods and results: We investigated the PETA family of HUNAN CHINA, gathered enough information for linkage analysis, in order to get a meaningful LOD score.We sequenced all 26 exons of SCN9A gene of the proband by obverse and reverse trend, and didn't find meaningful mutation, then selected 6 microsatellite markers (STR) in 2q24.1～24.3 and did linkage analysis in some of the family members, fond out that no linkage exists between PETA and D2S1353～D2S1776, ruled out the virulence gene locate in this range.
Conclusion: There is no SCN9A gene mutation in HUNAN PETA family, indicating new pathogenic gene. The new pathogenic gene loci is not in D2S1353～D2S1776.
目的:求证一湖南PETA家系是否具有新的致病基因,探讨新的致病基因位点是否位于2q24.1～24.3的D2S1353～D2S1776区间。
方法与结果:对一湖南PETA家系进行了调查,收集足够的家系资料,以便进行家系连锁分析得到有意义的LOD值。对该家系先症者进行SCN9A基因全部26个外显子正反向测序,未发现SCN9A异常突变,进而在2q24.1～24.3选取6个微卫星标记(STR),在部分家系成员中作连锁分析,排除该PETA家系致病基因定位于2q24.1～24.3的D2S1353～D2S1776区间。
结论:该湖南PETA家系不存在SCN9A基因外显子突变,提示有新的致病基因,新致病基因位点不在D2S1353～D2S1776区间。
Backgrounds: Primary erythromelalgia (PETA) is a rare disease act as autosomal dominant inheritance, characteristic mainly for the burning sensation of different levels of the end of limbs with the end of limb skin redness, often induced by the movement or temperature changes. Symptoms relief when expose to a low temperature environment such as cool water. The pathogenic mechanism is unclear, and there is no effective cure it by now. PETA bring serious physical and mental harm to patients and their family members. Some studies have mapped its virulence gene to 2q24.1～24.3, and found SCN9A is the virulence gene. The pathogenic mechanisms of SCN9A mutation is under studying. But in some PETA family, SCN9A mutation was not detected, suggesting genetic heterogeneity of PETA. Then searching for a new virulence gene become a research hot.
Obectives: To identify whether the PETA family of HUNAN has new disease gene and whether the gene loci is in 2q24.1～24.3.
Methods and results: We investigated the PETA family of HUNAN CHINA, gathered enough information for linkage analysis, in order to get a meaningful LOD score.We sequenced all 26 exons of SCN9A gene of the proband by obverse and reverse trend, and didn't find meaningful mutation, then selected 6 microsatellite markers (STR) in 2q24.1～24.3 and did linkage analysis in some of the family members, fond out that no linkage exists between PETA and D2S1353～D2S1776, ruled out the virulence gene locate in this range.
Conclusion: There is no SCN9A gene mutation in HUNAN PETA family, indicating new pathogenic gene. The new pathogenic gene loci is not in D2S1353～D2S1776.
引文
[1]李谋,余利红,刘小林,孙志贤,张成岗.原发性红斑性肢痛症致病基因研究进展.国外医学遗传学分册.2005,28(4):248-250
[2]Drenth JPH,Michiels JJ.Erythromelalgia and erythermalgia:diagnostic differentiation.Int J Dermatol,1994,33:393-397
[3]戚晓昆,朱克.红斑性肢痛及红热痛的诊断和治疗.中华神经科杂志[J].2001,34(1):41-45
[4]Novella SP,Hisama FM,Dib-Hajj SD,et al.A case of inherited erythromelalgia.Nat Clin Pract Neurol.2007 Apr;3(4):229-234
[5]Drenth JP,Finley WH,Breedveld GJ,et al.The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32.Am J Hum Genet 2001;68:1277-1282
[6]Yang Y,Wang Y,Li S,et al.Mutations in SCN9A,encoding a sodium channel alpha subunit,in patients with primary erythermalgia.J Med Genet 2004;41:71-174
[7]Drenth JP,te Morsche RH,Guillet G,et al.SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels.J Invest Dermatol.2005 Jun;124(6):1333-1338
[8]Lee MJ,Yu HS,Hsieh ST,et al.Characterization of a familial case with primary erythromelalgia from Taiwan.J Neurol.2007,254(2):210-204
[9]Dib-Hajj SD,Rush AM,Cummins TR,et al.Gain-of-function mutation in Nayl.7 in familial erythromelalgia induces bursting of sensory neurons.Brain.2005,128(Pt 8):1847-1854
[10]Waxman SG,Dib-Hajj SD.Erythromelalgia:a hereditary pain syndrome enters the molecular era.Ann Neurol.2005,57(6):785-788
[11]Oertel B,Lotsch J.Genetic mutations that prevent pain:implications for future pain medication.Pharmacogenomics.2008,9(2):179-194
[12]Krafte DS,Bannon AW.Sodium channels and nociception:recent concepts and therapeutic opportunities.Curr Opin Pharmacol.2008,8(1):50-56
[13]Drenth JP,Waxman SG.Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.J Clin Invest.2007,117(12):3603-3609
[14]Bums TM,Te Morsche RH,Jansen JB,Drenth JP.Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia.Br J Dermatol.2005,153(1):174-177
[15]Drenth JP,Te Morsche RH,Mansour S,et al.Primary erythermalgia as a sodium channelopathy:screening for SCN9A mutations:exclusion of a causal role of SCN10A and SCN11A.Arch Dermatol.2008,144(3):320-324
[16]杨微,刘兰英.人类的致病基因.生命的化学.2002,22(5):457-460
[17]廖成,赵慕钧,李载平.定位候选克隆.生命的化学.1999,19(2):92-94
[18]张咏莉,傅松滨.基因组扫描技术在医学遗传学研究中的应用国.国外医学遗传学分册.2001,24(3):154-158
[19]Weber JL,Broman KW.Genotyping for human whole-genome scans:past,present,and future.Adv Genet.2001;42:77-96
[20]Mellersh C.Microsatellite-based candidate gene linkage analysis studies.Methods Mol Biol.2008;439:75-86
[21]Butler JM.Short tandem repeat typing technologies used in human identity testing.Biotechniques.2007;43(4):ⅱ-ⅴ
[22]李东霞,苏秀兰.人类基因组的新型遗传标记:STR和SNP内蒙古医学院学报.2006,28(1):61-67
[23]Ghebranious N,Vaske D,Yu A,et al.STRP screening sets for the human genome at 5 cM density.BMC Genomics.2003,4(1):6
[24]Dausset J,Cann H,Cohen D,et al.Centre d'etude du polymorphisme humain(CEPH):collaborative genetic mapping of the human genome.Genomics.1990 Mar;6(3):575-577
[25]Cann HM.CEPH maps.Curt Opin Genet Dev.1992 Jun;2(3):393-399
[26]Kong X,Murphy K,Raj T,et al.A combined linkage-physical map of the human genome.Am J Hum Genet.2004 Dec;75(6):1143-1148
[27]江三多,吕宝忠.医学遗传数理统计方法.北京:科学出版社,1998:182-184
[28]Morton NE.LODs past and present.Genetics,1995,140:7-12
[29]吴超群.表观遗传学和人类疾病.中国优生优育.2007,13(13):112-119
[30]Brakhage AA,Schuemann J,Bergmann S,et al.Activation of fungal silent gene clusters:a new avenue to drug discovery.Prog Drug Res.2008;66:1,3-12
[31]黄庆,郭颖,府伟灵.人类表观基因组计划.生命的化学.2004,24(2):101-102
[32]Uysal-Onganer P,Djamgoz MB.Epidermal growth factor potentiates in vitro metastatic behaviour of human prostate cancer PC-3M cells:involvement of voltage-gated sodium channel.Mol Cancer.2007,24;6:76
[33]Rowat AC,Lammerding J,Herrmann H,et al.Towards an integrated understanding of the structure and mechanics of the cell nucleus.Bioessays. 20,08,30(3):226-236
[34]Mareotte EM,Pellegrini M,Ng HL,et al.Detecting protein function and protein-protein interactions from genome sequences.Science.1999,285(5428):751-753
[35]周冰燚,蒋玮莹.后基因组时代的功能基因组学.国际遗传学杂志.2007,30(4):261-264
[36]Moritz AL,Ji H,Schutz F,et al.A proteome strategy for fractionating proteins an d peptides using for continuous free-flow electrophoresis coupled of-line to reversed-phase high-performan celiquid chromatography.Anal Chem,2004,76:4811-4824
[37]Bader GD,Heilbut A,Andrens B,et al.Functional genomics and protemic:Charting a multidimensional map of the yeast cell.Trends Cell Biol.2003,13:344-356
[38]Wozniak RJ,Bresnick EH.Epigenetic control of complex loci during erythropoiesis.Curr Top Dev Biol.2008;82:55-83
[39]Pastinen T,Ge B,Hudson TJ.Influence of human genome polymorphism on gene expression.Hum Mol Genet.2006,15 Spec No1:R9-16
[40]Sambrook J,Russel D.Molecular Cloning:A Laboratry Manual(分子克隆实验指南,黄培堂等译).北京:科学出版社,2002.463-471
[41]Michiels JJ,te Morsche RH,Jansen JB,Drenth JP.Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Navl.7.Arch Neurol.2005 Oct;62(10):1587-1590
[42]Han C,Rush AM,Dib-Hajj SD,et al.Sporadic onset of erythermalgia:a gain-of-function mutation in Navl.7.Ann Neurol.2006 Mar;59(3):553-558
[43]Harty TP,Dib-Hajj SD,Tyrrell L,et al.Na(Ⅴ)1.7 mutant A863P in erythromelalgia:effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons.J Neurosci.2006 Nov 29;26(48):12566-12575
[44]Zhang LL,Lin ZM,Ma ZH,et al.Mutation hotspots of SCN9A in primary erythermalgia.Br.J Dermatol.2007 Apr;156(4):767-769
[45]Lee MJ,Yu HS,Hsieh ST,et al.Characterization of a familial case with primary erythromelalgia from Taiwan.J Neurol.2007 Feb;254(2):210-214
[46]Diss JK,Calissano M,Gascoyne D,et al.Identification and characterization of the promoter region of the Navl.7 voltage-gated sodium channel gene (SCN9A).Mol Cell Neurosci.2008,37(3):537-547
[47]Zhang LL,Lin ZM,Ma ZH,et al.Mutation hotspots of SCN9A in primary erythermalgia.Br J Dermatol.2007,156(4):767-769
[48]张安平,张学军,朱文元.疾病相关基因定位的全基因组扫描策略与方法.疾病控制杂志.2001,5(2):135-138
[1]Drenth JPH,Michiels JJ.Erythromelalgia and erythermalgia:diagnostic differentiation.Int J Dermatol,1994,33:393-397
[2]Michiels JJ,Drenth J.Classification and diagnosis of erythromelalgia and erythermalgia. Int J Dermatol ,1995, 34 :97-100
[3] Mork C, Kvernebo K, Asker CL, et al. Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism. J Invest Dermatol, 2002,119 (4) :781-782
[4] Kalgaard OM, Mork C, Kvernebo K. Prostacyclin reduces symptoms and sympathetic dysfunction in erythromelalgia in a double-blind randomized pilot study. Acta Derm Venereol, 2003,83 (6) :442-444
[5] Mork C, Salerud EG, Asker CL, et al. The prostaglandin El analog misoprostol reduces symptoms and microvascular arteriovenous shunting in erythromelalgia-a double-blind, crossover, placebo-compared study. J Invest Dermatol, 2004,122(3) .587-593
[6] Michiels JJ, Abels J, Steketee J, et al. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med , 1985 ,102(4) :466-471
[7] van Genderen PJ, Lucas IS, van Strik R. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost, 1996,76(3) :333-338
[8] Oliveira AS, Miranda MP, Duarte PC, et al. Essential thrombocythemia. Apropos a case of cerebrovascular stroke. Acta Med Port, 1933 ,6(10) .461-465
[9] Orstavik K, Mork C, Kvermebo K, et al. Pain in primary erythromelalgia-a neuropathic component ? Pain, 2004 ,110(3) :531-538
[10] Davis MD, Sandroni P, Rooke TW, et al. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol, 2003 ,139 (10): 1337-1343
[11] Sugiyama Y, Hakusui S, Takahashi A, et al. Parimary erythromelalgia :the role of skin sympathetic nerve activity. Jpn J Med, 1999,30 (6) :564-567
[12] Thami GP, Bhalla M. Erythromelalgia induced by possible calcium channel blockade by ciclosporin. BMJ, 2003 ,326(7395) :910-910
[13] Parish LC, Witkowski JA. Truncal morbilliform eruption due to nifedipine. Cutis, 1992 ,49(2): 113-114
[14] Ceulemans BP, Claes LR, Lagae LG. Clinical correlations of mutations in the SCNIA gene: frome febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol, 2004,30(4) :236-243
[15] Chan MK, Tucker AT, Madden S, et al. Erythromelalgia: an endothelial disorder responsive to sodium nitroprusside.Arch Dis Child,2002,87(3):229-230
[16]Drenth JP,Michiels JJ,Ozsoylu S.Acute secondary erythermalgia and hypertension in children.Eur J Pediatr,1995,154(11):882-885
[17]Zenz W,Zohrer B,Zobel G,et al.Acute erythromelalgia with hypertension in a 52 year old boy.Klin Padiatr,1999,211(6):469-472
[18]Drenth JP,Finley WH,Breedveld GJ,et al.The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32.Am J Hum Genet 2001,68:1277-1282
[19]Yang Y,Wang Y,Li S,et al.Mutations in SCN9A,encoding a sodium channel alpha subunit,in patients with primary erythermalgia.J Med Genet 2004,41:171-174
[20]Klugbauer N,Lacinova L,Flockerzi V,et al.Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.EMBO J,1995,14:1084-1090
[21]Toledo-Aral JJ,Moss BL,He ZJ,et al.Identification of PN1,a predominant voltage-dependent sodium channel expressed principally in peripheral neurons.Proc Natl Acad Sci U S A,1997,94:1527-1532
[22]Choi JS,Dib-Hajj SD,Waxman SG.Inherited erythermalgia:limb pain from an S4 charge-neutral Na channelopathy.Neurology,2006,67(9):1563-1567
[23]Han C,Lampert A,Rush AM,et al.Temperature dependence of erythromelalgia mutation L858F in sodium channel Navl.7.Mol Pain,2007,3:3
[24]戚晓昆,朱克.红斑性肢痛及红热痛的诊断和治疗.中华神经科杂志.2001,34(1):41-45
[25]Novella SP,Hisama FM,Dib-Hajj SD,et al.A case of inherited erythromelalgia.Nat Clin Pract Neurol.2007,3(4):229-234
[26]Drenth JP,te Morsche RH,Guillet G;et al.SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels.J Invest Dermatol.2005,124(6):1333-1338
[27]Burns TM,Te Morsche RH,Jansen JB,Drenth JP.Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia.Br J Dermatol.2005 Jul;153(1):174-1747
[1]G D'Arcangelo,K Paradiso,D Shepherd,et al.Neuronal growth factor regulation of two different sodium channel types through distinct signal transduction pathways.J Cell Biol,1993,122:915-921
[2]Klugbauer N,Lacinova L,Flockerzi V,et al.Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.EMBO J,1995,14:1084-1090
[3]Belcher,S.M.,Zerillo.C.A.,Levenson.R et al.Cloning of a sodium channel a subunit from rabbit Schwann cells.Proc Natl.Sci USA,1995,92:11034-11038
[4]Beckers MC,Emst E,Belcher S,et al.A new sodium channel alpha-subunit gene(Scn9a)from Schwann cells maps to the Scn1a,Scn2a,Scn3a cluster of mouse chromosome 2.Genomics,1996,36(1):202-205
[5]Sangameswaran L,Fish LM,Koch BD,et al.A novel tetrodotoxin-sensitive,voltage-gated sodium channel expressed in rat and human dorsal root ganglia.J Biol Chem,1997,272(23):14805-14809
[6] Toledo-Aral JJ, Moss BL, He ZJ, et al. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci U S A, 1997, 94:1527-1532
[7] Raymond CK, Castle J, Garrett-Engele P, et al. Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia. J Biol Chem, 2004, 279(44).46234-46241
[8] Alan L. Goldin. Evolution of voltage-gated Na+ channels. The Journal of Experimental Biology, 2002, 205 :575-584
[9] Cummins TR, Howe JR, Waxman SG Slow closed-state inactivation: a novel mechanism underlying ramp current in cells expressing the hNE/PN1 sodium channel. JNeurosci, 1998, 18:9606-9619
[10] Isom LL. Beta subunits: players in neuronal hyperexcitability? Novartis Found Symp, 2002, 241:124-138
[11] Drenth JPH , Michiels JJ . Erythromelalgia and erythermalgia : diagnostic differentiation. Int J Dermatol, 1994, 33:393-397
[12] Drenth JP, Finley WH, Breedveld GJ, et al. The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. Am J Hum Genet, 2001, 68(5): 1277-1282
[13] Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet, 2004, 41: 171-174
[14] Drenth JP, te Morsche RH, Guillet G, et al. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol, 2005, 124(6):1333-1338
[15] Dib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Navl.7 in familial erythromelalgia induces bursting of sensory neurons. Brain, 2005, 128(Pt 8):1847-1854
[16] Michiels JJ, te Morsche RH, Jansen JB, Drenth JP. Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Navl.7. Arch Neurol, 2005, 62(10): 1587-1590
[17] Han C, Rush AM, Dib-Hajj SD, et al. Sporadic onset of erythermalgia: a gain-of-function mutation in Navl.7. Ann Neurol, 2006 , 59(3):553-558
[18] Harty TP, Dib-Hajj SD, Tyrrell L, et al. Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J Neurosci, 2006, 26(48)12566-12575
[19] Zhang LL, Lin ZM, Ma ZH, et al. Mutation hotspots of SCN9A in primary erythermalgia. Br JDermatol, 2007, 156(4):767-769
[20] Lee MJ, Yu HS, Hsieh ST, et al. Characterization of a familial case with primary erythromelalgia from Taiwan. J Neurol, 2007 , 254(2):210-214
[21] Choi JS, Dib-Hajj SD, Waxman SG Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology, 2006, 67(9): 1563-1567
[22] Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG Size matters: Erythromelalgia mutation S241T in Navl.7 alters channel gating. J Biol Chem, 2006, 281(47):36029-36035
[23] Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Navl.7 sodium channels in a painful inherited neuropathy. J Neurosci, 2004, 24(38):8232-8336
[24] Rush AM, Dib-Hajj SD, Liu S, et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A, 2006, 103(21):8245-8250
[25] Han C, Lampert A, Rush AM, et al. Temperature dependence of erythromelalgia mutation L858F in sodium channel Navl.7. Mol Pain, 2007, 3:3
[26] Fertleman CR, Ferrie CD. What's in a name-familial rectal pain syndrome becomes paroxysmal extreme pain disorder.J Neurol Neurosurg Psychiatry, 2006, 77(11): 1294-1295
[27] Fertleman CR, Ferrie CD, Aicardi J, et al. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology. 2007, 69(6):586-595
[28] Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron, 2006, 52(5):767-74
[29] Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature, 2006 Dec 14;444(7121):894-898
[30] Goldberg. YP, MacFarlane J, MacDonald ML, et al. Loss-of-function mutations in the Navl.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet, 2007, 71(4):311-319
[31] Ahmad S, Dahllund L, Eriksson AB, et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet, 2007 , Jul 6; [Epub ahead of print]
[32] Nassar MA, Stirling LC, Forlani G, et al. Nociceptor-specific gene deletion reveals a major role for Navl.7 (PNl) in acute and inflammatory pain. Proc Natl Acad Sci U S A,2004, 101(34): 12706-12711
[33] Armen N. Akopian, Veronika Souslova, Steven England, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. nature neuroscience,1999, 2: 541-548
[34] Mohammed A Nassar, Alessandra Levato, L Caroline Stirling, et al. Neuropathic pain develops normally in mice lacking both Navl.7 and Nav1.8. Molecular Pain, 2005, 1:24
[35] Waxman SG, Dib-Hajj SD. Erythromelalgia: a hereditary pain syndrome enters the molecular era. Ann Neurol, 2005, 57(6):785-788
[2]Drenth JPH,Michiels JJ.Erythromelalgia and erythermalgia:diagnostic differentiation.Int J Dermatol,1994,33:393-397
[3]戚晓昆,朱克.红斑性肢痛及红热痛的诊断和治疗.中华神经科杂志[J].2001,34(1):41-45
[4]Novella SP,Hisama FM,Dib-Hajj SD,et al.A case of inherited erythromelalgia.Nat Clin Pract Neurol.2007 Apr;3(4):229-234
[5]Drenth JP,Finley WH,Breedveld GJ,et al.The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32.Am J Hum Genet 2001;68:1277-1282
[6]Yang Y,Wang Y,Li S,et al.Mutations in SCN9A,encoding a sodium channel alpha subunit,in patients with primary erythermalgia.J Med Genet 2004;41:71-174
[7]Drenth JP,te Morsche RH,Guillet G,et al.SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels.J Invest Dermatol.2005 Jun;124(6):1333-1338
[8]Lee MJ,Yu HS,Hsieh ST,et al.Characterization of a familial case with primary erythromelalgia from Taiwan.J Neurol.2007,254(2):210-204
[9]Dib-Hajj SD,Rush AM,Cummins TR,et al.Gain-of-function mutation in Nayl.7 in familial erythromelalgia induces bursting of sensory neurons.Brain.2005,128(Pt 8):1847-1854
[10]Waxman SG,Dib-Hajj SD.Erythromelalgia:a hereditary pain syndrome enters the molecular era.Ann Neurol.2005,57(6):785-788
[11]Oertel B,Lotsch J.Genetic mutations that prevent pain:implications for future pain medication.Pharmacogenomics.2008,9(2):179-194
[12]Krafte DS,Bannon AW.Sodium channels and nociception:recent concepts and therapeutic opportunities.Curr Opin Pharmacol.2008,8(1):50-56
[13]Drenth JP,Waxman SG.Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.J Clin Invest.2007,117(12):3603-3609
[14]Bums TM,Te Morsche RH,Jansen JB,Drenth JP.Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia.Br J Dermatol.2005,153(1):174-177
[15]Drenth JP,Te Morsche RH,Mansour S,et al.Primary erythermalgia as a sodium channelopathy:screening for SCN9A mutations:exclusion of a causal role of SCN10A and SCN11A.Arch Dermatol.2008,144(3):320-324
[16]杨微,刘兰英.人类的致病基因.生命的化学.2002,22(5):457-460
[17]廖成,赵慕钧,李载平.定位候选克隆.生命的化学.1999,19(2):92-94
[18]张咏莉,傅松滨.基因组扫描技术在医学遗传学研究中的应用国.国外医学遗传学分册.2001,24(3):154-158
[19]Weber JL,Broman KW.Genotyping for human whole-genome scans:past,present,and future.Adv Genet.2001;42:77-96
[20]Mellersh C.Microsatellite-based candidate gene linkage analysis studies.Methods Mol Biol.2008;439:75-86
[21]Butler JM.Short tandem repeat typing technologies used in human identity testing.Biotechniques.2007;43(4):ⅱ-ⅴ
[22]李东霞,苏秀兰.人类基因组的新型遗传标记:STR和SNP内蒙古医学院学报.2006,28(1):61-67
[23]Ghebranious N,Vaske D,Yu A,et al.STRP screening sets for the human genome at 5 cM density.BMC Genomics.2003,4(1):6
[24]Dausset J,Cann H,Cohen D,et al.Centre d'etude du polymorphisme humain(CEPH):collaborative genetic mapping of the human genome.Genomics.1990 Mar;6(3):575-577
[25]Cann HM.CEPH maps.Curt Opin Genet Dev.1992 Jun;2(3):393-399
[26]Kong X,Murphy K,Raj T,et al.A combined linkage-physical map of the human genome.Am J Hum Genet.2004 Dec;75(6):1143-1148
[27]江三多,吕宝忠.医学遗传数理统计方法.北京:科学出版社,1998:182-184
[28]Morton NE.LODs past and present.Genetics,1995,140:7-12
[29]吴超群.表观遗传学和人类疾病.中国优生优育.2007,13(13):112-119
[30]Brakhage AA,Schuemann J,Bergmann S,et al.Activation of fungal silent gene clusters:a new avenue to drug discovery.Prog Drug Res.2008;66:1,3-12
[31]黄庆,郭颖,府伟灵.人类表观基因组计划.生命的化学.2004,24(2):101-102
[32]Uysal-Onganer P,Djamgoz MB.Epidermal growth factor potentiates in vitro metastatic behaviour of human prostate cancer PC-3M cells:involvement of voltage-gated sodium channel.Mol Cancer.2007,24;6:76
[33]Rowat AC,Lammerding J,Herrmann H,et al.Towards an integrated understanding of the structure and mechanics of the cell nucleus.Bioessays. 20,08,30(3):226-236
[34]Mareotte EM,Pellegrini M,Ng HL,et al.Detecting protein function and protein-protein interactions from genome sequences.Science.1999,285(5428):751-753
[35]周冰燚,蒋玮莹.后基因组时代的功能基因组学.国际遗传学杂志.2007,30(4):261-264
[36]Moritz AL,Ji H,Schutz F,et al.A proteome strategy for fractionating proteins an d peptides using for continuous free-flow electrophoresis coupled of-line to reversed-phase high-performan celiquid chromatography.Anal Chem,2004,76:4811-4824
[37]Bader GD,Heilbut A,Andrens B,et al.Functional genomics and protemic:Charting a multidimensional map of the yeast cell.Trends Cell Biol.2003,13:344-356
[38]Wozniak RJ,Bresnick EH.Epigenetic control of complex loci during erythropoiesis.Curr Top Dev Biol.2008;82:55-83
[39]Pastinen T,Ge B,Hudson TJ.Influence of human genome polymorphism on gene expression.Hum Mol Genet.2006,15 Spec No1:R9-16
[40]Sambrook J,Russel D.Molecular Cloning:A Laboratry Manual(分子克隆实验指南,黄培堂等译).北京:科学出版社,2002.463-471
[41]Michiels JJ,te Morsche RH,Jansen JB,Drenth JP.Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Navl.7.Arch Neurol.2005 Oct;62(10):1587-1590
[42]Han C,Rush AM,Dib-Hajj SD,et al.Sporadic onset of erythermalgia:a gain-of-function mutation in Navl.7.Ann Neurol.2006 Mar;59(3):553-558
[43]Harty TP,Dib-Hajj SD,Tyrrell L,et al.Na(Ⅴ)1.7 mutant A863P in erythromelalgia:effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons.J Neurosci.2006 Nov 29;26(48):12566-12575
[44]Zhang LL,Lin ZM,Ma ZH,et al.Mutation hotspots of SCN9A in primary erythermalgia.Br.J Dermatol.2007 Apr;156(4):767-769
[45]Lee MJ,Yu HS,Hsieh ST,et al.Characterization of a familial case with primary erythromelalgia from Taiwan.J Neurol.2007 Feb;254(2):210-214
[46]Diss JK,Calissano M,Gascoyne D,et al.Identification and characterization of the promoter region of the Navl.7 voltage-gated sodium channel gene (SCN9A).Mol Cell Neurosci.2008,37(3):537-547
[47]Zhang LL,Lin ZM,Ma ZH,et al.Mutation hotspots of SCN9A in primary erythermalgia.Br J Dermatol.2007,156(4):767-769
[48]张安平,张学军,朱文元.疾病相关基因定位的全基因组扫描策略与方法.疾病控制杂志.2001,5(2):135-138
[1]Drenth JPH,Michiels JJ.Erythromelalgia and erythermalgia:diagnostic differentiation.Int J Dermatol,1994,33:393-397
[2]Michiels JJ,Drenth J.Classification and diagnosis of erythromelalgia and erythermalgia. Int J Dermatol ,1995, 34 :97-100
[3] Mork C, Kvernebo K, Asker CL, et al. Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism. J Invest Dermatol, 2002,119 (4) :781-782
[4] Kalgaard OM, Mork C, Kvernebo K. Prostacyclin reduces symptoms and sympathetic dysfunction in erythromelalgia in a double-blind randomized pilot study. Acta Derm Venereol, 2003,83 (6) :442-444
[5] Mork C, Salerud EG, Asker CL, et al. The prostaglandin El analog misoprostol reduces symptoms and microvascular arteriovenous shunting in erythromelalgia-a double-blind, crossover, placebo-compared study. J Invest Dermatol, 2004,122(3) .587-593
[6] Michiels JJ, Abels J, Steketee J, et al. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med , 1985 ,102(4) :466-471
[7] van Genderen PJ, Lucas IS, van Strik R. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost, 1996,76(3) :333-338
[8] Oliveira AS, Miranda MP, Duarte PC, et al. Essential thrombocythemia. Apropos a case of cerebrovascular stroke. Acta Med Port, 1933 ,6(10) .461-465
[9] Orstavik K, Mork C, Kvermebo K, et al. Pain in primary erythromelalgia-a neuropathic component ? Pain, 2004 ,110(3) :531-538
[10] Davis MD, Sandroni P, Rooke TW, et al. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol, 2003 ,139 (10): 1337-1343
[11] Sugiyama Y, Hakusui S, Takahashi A, et al. Parimary erythromelalgia :the role of skin sympathetic nerve activity. Jpn J Med, 1999,30 (6) :564-567
[12] Thami GP, Bhalla M. Erythromelalgia induced by possible calcium channel blockade by ciclosporin. BMJ, 2003 ,326(7395) :910-910
[13] Parish LC, Witkowski JA. Truncal morbilliform eruption due to nifedipine. Cutis, 1992 ,49(2): 113-114
[14] Ceulemans BP, Claes LR, Lagae LG. Clinical correlations of mutations in the SCNIA gene: frome febrile seizures to severe myoclonic epilepsy in infancy. Pediatr Neurol, 2004,30(4) :236-243
[15] Chan MK, Tucker AT, Madden S, et al. Erythromelalgia: an endothelial disorder responsive to sodium nitroprusside.Arch Dis Child,2002,87(3):229-230
[16]Drenth JP,Michiels JJ,Ozsoylu S.Acute secondary erythermalgia and hypertension in children.Eur J Pediatr,1995,154(11):882-885
[17]Zenz W,Zohrer B,Zobel G,et al.Acute erythromelalgia with hypertension in a 52 year old boy.Klin Padiatr,1999,211(6):469-472
[18]Drenth JP,Finley WH,Breedveld GJ,et al.The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32.Am J Hum Genet 2001,68:1277-1282
[19]Yang Y,Wang Y,Li S,et al.Mutations in SCN9A,encoding a sodium channel alpha subunit,in patients with primary erythermalgia.J Med Genet 2004,41:171-174
[20]Klugbauer N,Lacinova L,Flockerzi V,et al.Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.EMBO J,1995,14:1084-1090
[21]Toledo-Aral JJ,Moss BL,He ZJ,et al.Identification of PN1,a predominant voltage-dependent sodium channel expressed principally in peripheral neurons.Proc Natl Acad Sci U S A,1997,94:1527-1532
[22]Choi JS,Dib-Hajj SD,Waxman SG.Inherited erythermalgia:limb pain from an S4 charge-neutral Na channelopathy.Neurology,2006,67(9):1563-1567
[23]Han C,Lampert A,Rush AM,et al.Temperature dependence of erythromelalgia mutation L858F in sodium channel Navl.7.Mol Pain,2007,3:3
[24]戚晓昆,朱克.红斑性肢痛及红热痛的诊断和治疗.中华神经科杂志.2001,34(1):41-45
[25]Novella SP,Hisama FM,Dib-Hajj SD,et al.A case of inherited erythromelalgia.Nat Clin Pract Neurol.2007,3(4):229-234
[26]Drenth JP,te Morsche RH,Guillet G;et al.SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels.J Invest Dermatol.2005,124(6):1333-1338
[27]Burns TM,Te Morsche RH,Jansen JB,Drenth JP.Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia.Br J Dermatol.2005 Jul;153(1):174-1747
[1]G D'Arcangelo,K Paradiso,D Shepherd,et al.Neuronal growth factor regulation of two different sodium channel types through distinct signal transduction pathways.J Cell Biol,1993,122:915-921
[2]Klugbauer N,Lacinova L,Flockerzi V,et al.Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.EMBO J,1995,14:1084-1090
[3]Belcher,S.M.,Zerillo.C.A.,Levenson.R et al.Cloning of a sodium channel a subunit from rabbit Schwann cells.Proc Natl.Sci USA,1995,92:11034-11038
[4]Beckers MC,Emst E,Belcher S,et al.A new sodium channel alpha-subunit gene(Scn9a)from Schwann cells maps to the Scn1a,Scn2a,Scn3a cluster of mouse chromosome 2.Genomics,1996,36(1):202-205
[5]Sangameswaran L,Fish LM,Koch BD,et al.A novel tetrodotoxin-sensitive,voltage-gated sodium channel expressed in rat and human dorsal root ganglia.J Biol Chem,1997,272(23):14805-14809
[6] Toledo-Aral JJ, Moss BL, He ZJ, et al. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci U S A, 1997, 94:1527-1532
[7] Raymond CK, Castle J, Garrett-Engele P, et al. Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia. J Biol Chem, 2004, 279(44).46234-46241
[8] Alan L. Goldin. Evolution of voltage-gated Na+ channels. The Journal of Experimental Biology, 2002, 205 :575-584
[9] Cummins TR, Howe JR, Waxman SG Slow closed-state inactivation: a novel mechanism underlying ramp current in cells expressing the hNE/PN1 sodium channel. JNeurosci, 1998, 18:9606-9619
[10] Isom LL. Beta subunits: players in neuronal hyperexcitability? Novartis Found Symp, 2002, 241:124-138
[11] Drenth JPH , Michiels JJ . Erythromelalgia and erythermalgia : diagnostic differentiation. Int J Dermatol, 1994, 33:393-397
[12] Drenth JP, Finley WH, Breedveld GJ, et al. The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. Am J Hum Genet, 2001, 68(5): 1277-1282
[13] Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet, 2004, 41: 171-174
[14] Drenth JP, te Morsche RH, Guillet G, et al. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol, 2005, 124(6):1333-1338
[15] Dib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Navl.7 in familial erythromelalgia induces bursting of sensory neurons. Brain, 2005, 128(Pt 8):1847-1854
[16] Michiels JJ, te Morsche RH, Jansen JB, Drenth JP. Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Navl.7. Arch Neurol, 2005, 62(10): 1587-1590
[17] Han C, Rush AM, Dib-Hajj SD, et al. Sporadic onset of erythermalgia: a gain-of-function mutation in Navl.7. Ann Neurol, 2006 , 59(3):553-558
[18] Harty TP, Dib-Hajj SD, Tyrrell L, et al. Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J Neurosci, 2006, 26(48)12566-12575
[19] Zhang LL, Lin ZM, Ma ZH, et al. Mutation hotspots of SCN9A in primary erythermalgia. Br JDermatol, 2007, 156(4):767-769
[20] Lee MJ, Yu HS, Hsieh ST, et al. Characterization of a familial case with primary erythromelalgia from Taiwan. J Neurol, 2007 , 254(2):210-214
[21] Choi JS, Dib-Hajj SD, Waxman SG Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology, 2006, 67(9): 1563-1567
[22] Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG Size matters: Erythromelalgia mutation S241T in Navl.7 alters channel gating. J Biol Chem, 2006, 281(47):36029-36035
[23] Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Navl.7 sodium channels in a painful inherited neuropathy. J Neurosci, 2004, 24(38):8232-8336
[24] Rush AM, Dib-Hajj SD, Liu S, et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A, 2006, 103(21):8245-8250
[25] Han C, Lampert A, Rush AM, et al. Temperature dependence of erythromelalgia mutation L858F in sodium channel Navl.7. Mol Pain, 2007, 3:3
[26] Fertleman CR, Ferrie CD. What's in a name-familial rectal pain syndrome becomes paroxysmal extreme pain disorder.J Neurol Neurosurg Psychiatry, 2006, 77(11): 1294-1295
[27] Fertleman CR, Ferrie CD, Aicardi J, et al. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology. 2007, 69(6):586-595
[28] Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron, 2006, 52(5):767-74
[29] Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature, 2006 Dec 14;444(7121):894-898
[30] Goldberg. YP, MacFarlane J, MacDonald ML, et al. Loss-of-function mutations in the Navl.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet, 2007, 71(4):311-319
[31] Ahmad S, Dahllund L, Eriksson AB, et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet, 2007 , Jul 6; [Epub ahead of print]
[32] Nassar MA, Stirling LC, Forlani G, et al. Nociceptor-specific gene deletion reveals a major role for Navl.7 (PNl) in acute and inflammatory pain. Proc Natl Acad Sci U S A,2004, 101(34): 12706-12711
[33] Armen N. Akopian, Veronika Souslova, Steven England, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. nature neuroscience,1999, 2: 541-548
[34] Mohammed A Nassar, Alessandra Levato, L Caroline Stirling, et al. Neuropathic pain develops normally in mice lacking both Navl.7 and Nav1.8. Molecular Pain, 2005, 1:24
[35] Waxman SG, Dib-Hajj SD. Erythromelalgia: a hereditary pain syndrome enters the molecular era. Ann Neurol, 2005, 57(6):785-788