宁夏地区遗传性脊髓小脑性共济失调3型的临床与分子研究
|
摘要
目的:调查宁夏地区临床诊断为脊髓小脑共济失调(SCAs)的11个家系,对家系患者及成员进行SCA3基因(CAG)n三核苷酸重复数目的检测分析。
方法:为33名家系患者、54名家系直系亲属及30名正常对照者进行SCA1、SCA2、SCA3、SCA6、SCA7基因(CAG)n三核苷酸重复数目的检测分析。基因检测方法:取外周静脉血提取基因组DNA为模板,行基因目的片段PCR扩增,经琼脂糖凝胶电泳后切取异常扩增片段经自动测序仪行测序分析,读取CAG扩增片段长度。
结果(:1)11个宁夏籍SCAs家系的所有受检患者经基因检测有8个家系确诊为SCA3型(其中有两个回族家系),另3个家系由于实验室条件限制,没有明确亚型,但已排除SCA1、SCA2、SCA3、SCA6、SCA7型。此8个家系的受检患者共有26例,符合常染色体显性遗传规律,其发病年龄21-50岁,均以小脑性共济失调与构音障碍为突出表现。(2)分子生物学检查结果:正常对照SCA3基因(CAG)n重复数目为10-34次,在正常范围,8个明确诊断为SCA3家系的30例患者(CAG)n重复数目为68-80次,与正常对照有显著性差异(P<0.001);患者子女中共有18例无症状者的一条等位基因(CAG)n重复数为68-78次,明确诊断为SCA3症状前患者。
结论:(1)11个SCAs家系患者的临床表现复杂,有明显的临床异质性,单纯根据临床表现很难将其具体分型;(2)系统报道我国宁夏地区SCA3亚型及其临床特征,并发现SCA3可能是宁夏地区较常见的SCAs亚型;(3)(CAG)n拷贝数与发病年龄呈负相关;(4)(CAG)n重复数反应了病情进展速度和预后,(CAG)n拷贝数越大病情进展越快,预后越差;(5)SCA3突变基因监测可以准确的诊断出SCAs症状前患者;(6)回汉族家系患者临床表现无明显差异,(CAG)n重复数无显著性差异。
Objectives The aims of the present investigation were:to investigate the clinical manifestation of Ningxia province for the clinical diagnosis of late-onset ataxia for the hereditary spinocerebellar ataxia of 11 families, and analysed the (CAG) n repeats in the SCA3 gene of the patients and their family members
Methods To analyse the CAG repeats in the SCA1, SCA2, SCA3、SCA6、SCA7 gene of 33 patients, 54 family members and 30 normal controls. Genetic Testing Methods:Peripheral blood was collected from patients and their relatives. Use the genomic DNA as a template,Molecular analysis were performed by PCR amplification using the published primer sequences of SCA3/MJD,and the allele trinucleotide repeat sizes of CAG products were determined by GeneScan Analyzer and DNA sequencing.
Results (1) Among the eleven investigated families,we have found 8 families with an abnormal expansion at the SCA3 locus (of which there are two Hui People) and the other three families as a result of laboratory conditions, there is no clear subtype , but has ruled out the SCA1、SCA2、SCA3、SCA6、SCA7 type. (2) molecular biology test results: normal SCA3 alleles of control individuals contained from 10 to 34 repeats, but 30 affected patients and 18 relatives who without any symptom had an abnormal expansion showing from 68 to 80 CAG repeats. The normal control individuals were significantly different (P <0.001); patients with a total of 18 cases of children from a silent allele (CAG) n Repeat for 68-78 times, significantly exceeded the normal range, a clear diagnosis for patients before symptoms SCA3.
Conclusion (1) 11 SCAS pedigree of patients with clinical manifestations of the complex, there are obvious clinical heterogeneity, it is very difficult based on clinical performance of its specific sub-type; (2) SCA3 Ningxia region may be more common subtype SCAS; (3) (CAG) n copy number and age of onset was negatively correlated; (4) (CAG) n repeat numbers reflect the rate of progress and prognosis of the disease, (CAG) n copy number the greater the disease sooner, the worse the prognosis; (5) SCA3 monitoring mutant gene can accurately diagnose the patients before symptoms SCAS; (6) back to the Han family clinical manifestations in patients with no significant difference, (CAG) n repeat numbers was no significant difference.
方法:为33名家系患者、54名家系直系亲属及30名正常对照者进行SCA1、SCA2、SCA3、SCA6、SCA7基因(CAG)n三核苷酸重复数目的检测分析。基因检测方法:取外周静脉血提取基因组DNA为模板,行基因目的片段PCR扩增,经琼脂糖凝胶电泳后切取异常扩增片段经自动测序仪行测序分析,读取CAG扩增片段长度。
结果(:1)11个宁夏籍SCAs家系的所有受检患者经基因检测有8个家系确诊为SCA3型(其中有两个回族家系),另3个家系由于实验室条件限制,没有明确亚型,但已排除SCA1、SCA2、SCA3、SCA6、SCA7型。此8个家系的受检患者共有26例,符合常染色体显性遗传规律,其发病年龄21-50岁,均以小脑性共济失调与构音障碍为突出表现。(2)分子生物学检查结果:正常对照SCA3基因(CAG)n重复数目为10-34次,在正常范围,8个明确诊断为SCA3家系的30例患者(CAG)n重复数目为68-80次,与正常对照有显著性差异(P<0.001);患者子女中共有18例无症状者的一条等位基因(CAG)n重复数为68-78次,明确诊断为SCA3症状前患者。
结论:(1)11个SCAs家系患者的临床表现复杂,有明显的临床异质性,单纯根据临床表现很难将其具体分型;(2)系统报道我国宁夏地区SCA3亚型及其临床特征,并发现SCA3可能是宁夏地区较常见的SCAs亚型;(3)(CAG)n拷贝数与发病年龄呈负相关;(4)(CAG)n重复数反应了病情进展速度和预后,(CAG)n拷贝数越大病情进展越快,预后越差;(5)SCA3突变基因监测可以准确的诊断出SCAs症状前患者;(6)回汉族家系患者临床表现无明显差异,(CAG)n重复数无显著性差异。
Objectives The aims of the present investigation were:to investigate the clinical manifestation of Ningxia province for the clinical diagnosis of late-onset ataxia for the hereditary spinocerebellar ataxia of 11 families, and analysed the (CAG) n repeats in the SCA3 gene of the patients and their family members
Methods To analyse the CAG repeats in the SCA1, SCA2, SCA3、SCA6、SCA7 gene of 33 patients, 54 family members and 30 normal controls. Genetic Testing Methods:Peripheral blood was collected from patients and their relatives. Use the genomic DNA as a template,Molecular analysis were performed by PCR amplification using the published primer sequences of SCA3/MJD,and the allele trinucleotide repeat sizes of CAG products were determined by GeneScan Analyzer and DNA sequencing.
Results (1) Among the eleven investigated families,we have found 8 families with an abnormal expansion at the SCA3 locus (of which there are two Hui People) and the other three families as a result of laboratory conditions, there is no clear subtype , but has ruled out the SCA1、SCA2、SCA3、SCA6、SCA7 type. (2) molecular biology test results: normal SCA3 alleles of control individuals contained from 10 to 34 repeats, but 30 affected patients and 18 relatives who without any symptom had an abnormal expansion showing from 68 to 80 CAG repeats. The normal control individuals were significantly different (P <0.001); patients with a total of 18 cases of children from a silent allele (CAG) n Repeat for 68-78 times, significantly exceeded the normal range, a clear diagnosis for patients before symptoms SCA3.
Conclusion (1) 11 SCAS pedigree of patients with clinical manifestations of the complex, there are obvious clinical heterogeneity, it is very difficult based on clinical performance of its specific sub-type; (2) SCA3 Ningxia region may be more common subtype SCAS; (3) (CAG) n copy number and age of onset was negatively correlated; (4) (CAG) n repeat numbers reflect the rate of progress and prognosis of the disease, (CAG) n copy number the greater the disease sooner, the worse the prognosis; (5) SCA3 monitoring mutant gene can accurately diagnose the patients before symptoms SCAS; (6) back to the Han family clinical manifestations in patients with no significant difference, (CAG) n repeat numbers was no significant difference.
引文
[1]段晓慧,顾卫红,王国相.常染色体显性遗传脊髓小脑性共济失调表型和基因型的相关性中日友好医院学报2008年第22卷第1期
[2] Takano H,Cancel G,et al.Close association between dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.Am J Hum Genet,1998,63:1060-1066
[3] KawaguchiY, OkamotoT, TaniwakiM, eta.l CAG expansions in a novelgene for Machado-Joseph disease atchrom osome 14q32. 1 [J].NatGenet, 1994, 8: 221.
[4] Schols L, Bauer P, Schmidt T, et al.Autosomal dominant cerebellar ataxias: Clinical features, genetics, and patho genesis[J]. LancetNeuro,l 2004, 3: 291-304.
[5] Manto M -U. The wide spectrum of spinocerebellar ataxia[J]. Cerebellum. 2005, 4(1): 2-6
[6] Duenas AM,GooldR, Giunti P.Molecular pathogenesis of spinocerebellar ataxias[J]. Brain, 2006, 129: 1357-1370.
[7] Yu Koyama & Masato Asahina & Koiti Honma Altered Heart Rate Control in Response to Postural Change in Patients with Machado–Joseph Disease (SCA3) Cerebellum DOI 10.1007/s12311-008-0076-2
[8] ChungM,RaxlurnLPW,DuricklLA,et al.Evidence for a rnaeharlism predisposing to intergenerational CAG repeat instabilily in spinocerebellar ataxia typeI.Nature Genet 1993:5:254.
[9] Lindenberg KS,Yvert G,Muller K,et al.Expression analysis of ataxin-7Mrna and protein in human brain;evidence for a widespread distribution and focal protein accumulation.Briain pothol,2000;10:385.
[10]张小宁,汪师贞.脊髓小脑性共济失调的研究进展新疆医学2006年第36卷206-210
[11] Cagnoli C,Mariotti C,Taroni F, et al. SCA28, a novel form of autoso-mal dominantcerebellar ataxia on chromosome 18p11. 22-q11. 2[J].Brain, 2006, 129: 235-242.
[12] Tang BS,Liu CY, Shen L, eta.l Frequency ofSCA-1, SCA-2, SCA-3 /MJD, SCA-6, SCA-7, and DRPLA CAG trinucleotide repeat expansionin patients with hereditary spinocerebellar ataxia from Chinese kindreds [J].ArchNeuro,l 2000, 57: 540.
[13] Sasaki H,Yake I,Tashiro K.The hereditary spinocerebellar ataxias inJapan[J]. CytogenetGenome Res, 2003, 100: 198-205.
[14]韩燕,管阳太,郑惠民.脊髓小脑性共济失调3型的临床与分子生物学特征临床神经病学杂志2007年第20卷第6期417-419
[15] K.Burk C.Globas et Cognitive deficits in spinocerebellar ataxia type 1、2、3[J].Neurol(2003)250:207-211
[16] Abele M, Burk K, Laccone F, eta.l Restless legs syndrome in spinocerebellar ataxia types1, 2 and 3[J]. JNeuro,l 2001, 248: 311
[17] Dürr A, Stevanin G, Cancel G, et al. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol, 1996, 39:490-499.
[18] Sakai T, Kawakami H. Machado-Joseph disease: a proposal of spastic paraplegic subtype. Neurology, 1996, 46:846-847.
[19] Tuite PJ, Rogaeva EA, St George-Hyslop PH, et al. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol, 1995, 38:684-687.
[20] Rosenberg RN, Fowler HL. Autosomal dominant motor system disease of the Portuguese: a review. Neurology, 1981, 31:1124-1126.
[21]顾卫红,王国相,王康等.脊髓小脑共济失调3型临床变异型特征及突变分析中国现代神经疾病杂志2008年4月第8卷第2期Chin J Contemp Neurol Neurosurg, April 2008, Vol. 8, No. 2 134-138.
[22]王相国周永兴李玉芬等Machado-Joseph病中国家系的临床和病理研究中华神经科杂志1996;29;293-296
[23]王相国周永兴李玉芬等Machado-Joseph病中国家系的临床和病理研究中华神经科杂志1997;14(1);1
[24] Schmitz-Hubsch T, Tezenas du Montcel S , Baliko L, et al.Reliability and validity of the International Cooperative Ataxia RatingScale : a study in 156 spinocerebellar ataxia patients . Mov Disord 2006;21(5):699-704
[25] Storey E, Tuck K, Hester R, et al. Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS). Mov Disord 2004;19(2):190-192
[26] Cano SJ, Hobart JC, Hart PE, et al. International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich's ataxia?Mov Disord 2005;20(12):1585-1591
[27]谢秋幼梁秀龄李沟桦等脊髓小脑性共济失调的分子生物学发病机制国外医学内科学分册2003年12月第30卷第12期507-523.
[28] PanigrahiGB,Cleary JD,Pearson CE、etal.[J].J Biol Chem,2002,277:13926-13934,
[29] Sinden RR.[J」.Nature,200l,411:757-758
[30] Cleary JD,Niehol K,Wang YH,et al.[J].Nat Genet,2002,31:37-46.
[31] Jankowski C,Nag DK. [J].Mol Genet Genomies,2002,267:64-70.
[32]朴钟源宋琳江新梅脊髓小脑性共济失调的分型进展进展中风与神经疾病杂志2008,Vol25,No. 4 504-506
[33] MichalikA, Van Broeckhoven C. Pathogenesis of polyglutaminedisorders: aggregation revisited[J].HumMolGenet, 2003, 12(2):173-186.
[34] YamadaM, SatoT,Tsuji S,et al. CAG repeat disordermodels andhuman neuropathology: similarities and differences[J].Acta Neu-ropatho,l 2008, 115(1): 71-86.
[35] IshikawaK, FujigasakiH, Saegusa H,et al. Abundant expressionand cytoplasmic aggregations of alpha 1A voltage-dependent calci-um channelprotein associatedwith neurodegeneration in spinocere-bellar ataxia type 6[J].HumMolGenet, 1999, 8(7):1185-1193.
[36]谭建强袁志刚脊髓小脑性共济失调分子遗传学研究进展医学综述2008年10月第14卷第20期MedicalRecapitulate,Oct2008,Vo.l 14,No. 20 3058-3060
[41][37] Olaf Riess, Udo RU¨B2, Annalisa PastoreSCA3:Neurological features, pathogenesis and animal models The Crerbellum 2008,125-137
[38] Chen DH ,Brkanac Z,Verlinde CL,et al.Missense mutation in the regulatory domain of PKC gamma:a new mechanism for dominant nonepisodic cerebellar ataxia.Am J Hum Genet 2003;72:839-849
[39] Zhou YX,Takiyama Y,Wang GX,et al.Machado-Joseph disease in four Chinese pedigrees:Molecular analysis of 15 patients including of two juvenile cases and clinical correlations.Neurology,1997,48:482-485
[40]姜淼,金春连,林长坤等。东北地区正常汉族人群SCA1及SCA3/MJD基因内CAG重复变异研究。中华医学遗传学杂志。2004年2月第21卷第一期。
[1] DuenasAM,Goold R, Giunti P.Molecular pathogenesis of spinocere-bellar ataxias[J]. Brain, 2006, 129: 1357-1370.
[2] Bryer A, Krause A, Bill P, et al.The hereditary adult onset ataxias in South Africa[J].J Neurol Sci, 2003, 216:47- 54
[3] Ludger S, Peter B, Thorsten S, et al.Autosomal dominant cerebellar ataxias:clinical features genetics and pathogenesis[J].Lancet Neurol, 2004, 3:291- 304
[4] K.Burk C.Globas et Cognitive deficits in spinocerebellar ataxia type 1,2,3[J].Neurol(2003)250:207-211
[5]江泓,唐北沙.脊髓小脑性共济失调的临床及基因诊断进展Forergn Medical Sciences on Neurology 2002,29(4).290-293
[6] RosaAL,AshizawaT.Gentieataxia.NeurolClin,2002,20(3):727~757
[8] Tan EK,Ashizawa Gentic testing in spinocerebellar ataxias defining a clinical role.Arch Neurol,2001,58(2),191-195
[9] Esteban E, Rodon N, Via M,et al. Androgen receptor CAG andGGC polymorphisms inMediterraneans: repeatdynamics and popu-lation relationships[J]. JHum Genet, 2006, 51(2): 129-136.
[10] Michalik A, Van Broeckhoven C. Pathogenesis of polyglutaminedisorders: aggregation revisited[J].HumMolGenet, 2003, 12(2):173-186.
[11] Yamada M, SatoT,Tsuji S,et al. CAG repeat disorder models and human neuropathology: similarities and differences[J].Acta Neu-ropatho,l 2008, 115(1): 71-86.
[12] Ishikawa K, Fujigasaki H, Saegusa H,et al. Abundant expression and cytoplasmic aggregations of alpha 1A voltage-dependent calcium channelprotein associated with neurode generation in spinocerebellar ataxia type 6[J].HumMolGenet, 1999, 8(7): 1185-1193.
[7][13]谭建强,袁志刚.脊髓小脑性共济失调分子遗传学研究进展医学综述2008年10月第14卷第20期MedicalRecapitulate,Oct2008,Vo.l 14,No. 20 3058-3060
[14] DeMichele G,CoppolaG,Cocozza S,etal.A pathogenetic classifi-cation ofhereditary ataxias: is the time ripe? [J]. JNeuro,l 2004,251(8): 913-922.
[15] Mochizuki Y,Kawata A,Mizutani T,et al.Hereditary paroxysmal ataxia with mental retardation: a clinical pathological study in relation to episodic ataxia type 2 [ J]. Acta Neuropatho,l 2004, 108(4): 345-349.
[16]杨华艳,陈宜张.骨骼肌-神经系统离子通道病基础医学与临床2005年11月第25卷第11期
[17] Lin X,Ashizawa T.Recent progress in spinocerebellar ataxia type-10 (SCA10)[J].Cerebellum, 2005, 4(1): 37-42.
[18]朴钟源,宋琳等.脊髓小脑性共济失调的分型进展中风与神经疾病杂志2008,Vol25,No. 4 504-506
[19] Cagnoli C,Mariotti C,Taroni F, et a.l SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11. 22-q11. 2[J].Brain, 2006, 129: 235-242.
[20]谢秋幼,梁秀龄,李洵桦.脊髓小脑性共济失调的分子遗传学诊断与临床应用中华医学遗传学杂志2005年2月第22卷第1期Chin J Med Genet, February 2005, Vol. 22, No.1
[21] Tsai HF,Liu CS,Chen GD,et al.Prenatal diagnosis ofMachado-Joseph disease/Spinocerebellar Ataxia Type 3in Taiwan:early detection of expanded ataxin-3[J].J ClinLab Anal,2003,17(5):195
[22] Yusaku Shimizu Kunihiro Yoshida Tomomi Okano et al. Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysisof 86 families. J Hum Genet (2004) 49:610–616. DOI 10.1007/s10038-004-0196-6
[23] Takano H,Cancel G,et al.Close association between dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.Am J Hum Genet,1998,63:1060-1066
[2] Takano H,Cancel G,et al.Close association between dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.Am J Hum Genet,1998,63:1060-1066
[3] KawaguchiY, OkamotoT, TaniwakiM, eta.l CAG expansions in a novelgene for Machado-Joseph disease atchrom osome 14q32. 1 [J].NatGenet, 1994, 8: 221.
[4] Schols L, Bauer P, Schmidt T, et al.Autosomal dominant cerebellar ataxias: Clinical features, genetics, and patho genesis[J]. LancetNeuro,l 2004, 3: 291-304.
[5] Manto M -U. The wide spectrum of spinocerebellar ataxia[J]. Cerebellum. 2005, 4(1): 2-6
[6] Duenas AM,GooldR, Giunti P.Molecular pathogenesis of spinocerebellar ataxias[J]. Brain, 2006, 129: 1357-1370.
[7] Yu Koyama & Masato Asahina & Koiti Honma Altered Heart Rate Control in Response to Postural Change in Patients with Machado–Joseph Disease (SCA3) Cerebellum DOI 10.1007/s12311-008-0076-2
[8] ChungM,RaxlurnLPW,DuricklLA,et al.Evidence for a rnaeharlism predisposing to intergenerational CAG repeat instabilily in spinocerebellar ataxia typeI.Nature Genet 1993:5:254.
[9] Lindenberg KS,Yvert G,Muller K,et al.Expression analysis of ataxin-7Mrna and protein in human brain;evidence for a widespread distribution and focal protein accumulation.Briain pothol,2000;10:385.
[10]张小宁,汪师贞.脊髓小脑性共济失调的研究进展新疆医学2006年第36卷206-210
[11] Cagnoli C,Mariotti C,Taroni F, et al. SCA28, a novel form of autoso-mal dominantcerebellar ataxia on chromosome 18p11. 22-q11. 2[J].Brain, 2006, 129: 235-242.
[12] Tang BS,Liu CY, Shen L, eta.l Frequency ofSCA-1, SCA-2, SCA-3 /MJD, SCA-6, SCA-7, and DRPLA CAG trinucleotide repeat expansionin patients with hereditary spinocerebellar ataxia from Chinese kindreds [J].ArchNeuro,l 2000, 57: 540.
[13] Sasaki H,Yake I,Tashiro K.The hereditary spinocerebellar ataxias inJapan[J]. CytogenetGenome Res, 2003, 100: 198-205.
[14]韩燕,管阳太,郑惠民.脊髓小脑性共济失调3型的临床与分子生物学特征临床神经病学杂志2007年第20卷第6期417-419
[15] K.Burk C.Globas et Cognitive deficits in spinocerebellar ataxia type 1、2、3[J].Neurol(2003)250:207-211
[16] Abele M, Burk K, Laccone F, eta.l Restless legs syndrome in spinocerebellar ataxia types1, 2 and 3[J]. JNeuro,l 2001, 248: 311
[17] Dürr A, Stevanin G, Cancel G, et al. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol, 1996, 39:490-499.
[18] Sakai T, Kawakami H. Machado-Joseph disease: a proposal of spastic paraplegic subtype. Neurology, 1996, 46:846-847.
[19] Tuite PJ, Rogaeva EA, St George-Hyslop PH, et al. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol, 1995, 38:684-687.
[20] Rosenberg RN, Fowler HL. Autosomal dominant motor system disease of the Portuguese: a review. Neurology, 1981, 31:1124-1126.
[21]顾卫红,王国相,王康等.脊髓小脑共济失调3型临床变异型特征及突变分析中国现代神经疾病杂志2008年4月第8卷第2期Chin J Contemp Neurol Neurosurg, April 2008, Vol. 8, No. 2 134-138.
[22]王相国周永兴李玉芬等Machado-Joseph病中国家系的临床和病理研究中华神经科杂志1996;29;293-296
[23]王相国周永兴李玉芬等Machado-Joseph病中国家系的临床和病理研究中华神经科杂志1997;14(1);1
[24] Schmitz-Hubsch T, Tezenas du Montcel S , Baliko L, et al.Reliability and validity of the International Cooperative Ataxia RatingScale : a study in 156 spinocerebellar ataxia patients . Mov Disord 2006;21(5):699-704
[25] Storey E, Tuck K, Hester R, et al. Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS). Mov Disord 2004;19(2):190-192
[26] Cano SJ, Hobart JC, Hart PE, et al. International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich's ataxia?Mov Disord 2005;20(12):1585-1591
[27]谢秋幼梁秀龄李沟桦等脊髓小脑性共济失调的分子生物学发病机制国外医学内科学分册2003年12月第30卷第12期507-523.
[28] PanigrahiGB,Cleary JD,Pearson CE、etal.[J].J Biol Chem,2002,277:13926-13934,
[29] Sinden RR.[J」.Nature,200l,411:757-758
[30] Cleary JD,Niehol K,Wang YH,et al.[J].Nat Genet,2002,31:37-46.
[31] Jankowski C,Nag DK. [J].Mol Genet Genomies,2002,267:64-70.
[32]朴钟源宋琳江新梅脊髓小脑性共济失调的分型进展进展中风与神经疾病杂志2008,Vol25,No. 4 504-506
[33] MichalikA, Van Broeckhoven C. Pathogenesis of polyglutaminedisorders: aggregation revisited[J].HumMolGenet, 2003, 12(2):173-186.
[34] YamadaM, SatoT,Tsuji S,et al. CAG repeat disordermodels andhuman neuropathology: similarities and differences[J].Acta Neu-ropatho,l 2008, 115(1): 71-86.
[35] IshikawaK, FujigasakiH, Saegusa H,et al. Abundant expressionand cytoplasmic aggregations of alpha 1A voltage-dependent calci-um channelprotein associatedwith neurodegeneration in spinocere-bellar ataxia type 6[J].HumMolGenet, 1999, 8(7):1185-1193.
[36]谭建强袁志刚脊髓小脑性共济失调分子遗传学研究进展医学综述2008年10月第14卷第20期MedicalRecapitulate,Oct2008,Vo.l 14,No. 20 3058-3060
[41][37] Olaf Riess, Udo RU¨B2, Annalisa PastoreSCA3:Neurological features, pathogenesis and animal models The Crerbellum 2008,125-137
[38] Chen DH ,Brkanac Z,Verlinde CL,et al.Missense mutation in the regulatory domain of PKC gamma:a new mechanism for dominant nonepisodic cerebellar ataxia.Am J Hum Genet 2003;72:839-849
[39] Zhou YX,Takiyama Y,Wang GX,et al.Machado-Joseph disease in four Chinese pedigrees:Molecular analysis of 15 patients including of two juvenile cases and clinical correlations.Neurology,1997,48:482-485
[40]姜淼,金春连,林长坤等。东北地区正常汉族人群SCA1及SCA3/MJD基因内CAG重复变异研究。中华医学遗传学杂志。2004年2月第21卷第一期。
[1] DuenasAM,Goold R, Giunti P.Molecular pathogenesis of spinocere-bellar ataxias[J]. Brain, 2006, 129: 1357-1370.
[2] Bryer A, Krause A, Bill P, et al.The hereditary adult onset ataxias in South Africa[J].J Neurol Sci, 2003, 216:47- 54
[3] Ludger S, Peter B, Thorsten S, et al.Autosomal dominant cerebellar ataxias:clinical features genetics and pathogenesis[J].Lancet Neurol, 2004, 3:291- 304
[4] K.Burk C.Globas et Cognitive deficits in spinocerebellar ataxia type 1,2,3[J].Neurol(2003)250:207-211
[5]江泓,唐北沙.脊髓小脑性共济失调的临床及基因诊断进展Forergn Medical Sciences on Neurology 2002,29(4).290-293
[6] RosaAL,AshizawaT.Gentieataxia.NeurolClin,2002,20(3):727~757
[8] Tan EK,Ashizawa Gentic testing in spinocerebellar ataxias defining a clinical role.Arch Neurol,2001,58(2),191-195
[9] Esteban E, Rodon N, Via M,et al. Androgen receptor CAG andGGC polymorphisms inMediterraneans: repeatdynamics and popu-lation relationships[J]. JHum Genet, 2006, 51(2): 129-136.
[10] Michalik A, Van Broeckhoven C. Pathogenesis of polyglutaminedisorders: aggregation revisited[J].HumMolGenet, 2003, 12(2):173-186.
[11] Yamada M, SatoT,Tsuji S,et al. CAG repeat disorder models and human neuropathology: similarities and differences[J].Acta Neu-ropatho,l 2008, 115(1): 71-86.
[12] Ishikawa K, Fujigasaki H, Saegusa H,et al. Abundant expression and cytoplasmic aggregations of alpha 1A voltage-dependent calcium channelprotein associated with neurode generation in spinocerebellar ataxia type 6[J].HumMolGenet, 1999, 8(7): 1185-1193.
[7][13]谭建强,袁志刚.脊髓小脑性共济失调分子遗传学研究进展医学综述2008年10月第14卷第20期MedicalRecapitulate,Oct2008,Vo.l 14,No. 20 3058-3060
[14] DeMichele G,CoppolaG,Cocozza S,etal.A pathogenetic classifi-cation ofhereditary ataxias: is the time ripe? [J]. JNeuro,l 2004,251(8): 913-922.
[15] Mochizuki Y,Kawata A,Mizutani T,et al.Hereditary paroxysmal ataxia with mental retardation: a clinical pathological study in relation to episodic ataxia type 2 [ J]. Acta Neuropatho,l 2004, 108(4): 345-349.
[16]杨华艳,陈宜张.骨骼肌-神经系统离子通道病基础医学与临床2005年11月第25卷第11期
[17] Lin X,Ashizawa T.Recent progress in spinocerebellar ataxia type-10 (SCA10)[J].Cerebellum, 2005, 4(1): 37-42.
[18]朴钟源,宋琳等.脊髓小脑性共济失调的分型进展中风与神经疾病杂志2008,Vol25,No. 4 504-506
[19] Cagnoli C,Mariotti C,Taroni F, et a.l SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11. 22-q11. 2[J].Brain, 2006, 129: 235-242.
[20]谢秋幼,梁秀龄,李洵桦.脊髓小脑性共济失调的分子遗传学诊断与临床应用中华医学遗传学杂志2005年2月第22卷第1期Chin J Med Genet, February 2005, Vol. 22, No.1
[21] Tsai HF,Liu CS,Chen GD,et al.Prenatal diagnosis ofMachado-Joseph disease/Spinocerebellar Ataxia Type 3in Taiwan:early detection of expanded ataxin-3[J].J ClinLab Anal,2003,17(5):195
[22] Yusaku Shimizu Kunihiro Yoshida Tomomi Okano et al. Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysisof 86 families. J Hum Genet (2004) 49:610–616. DOI 10.1007/s10038-004-0196-6
[23] Takano H,Cancel G,et al.Close association between dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations.Am J Hum Genet,1998,63:1060-1066