遗传性痉挛性截瘫患者致病基因突变特征及其与临床表型的关系
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摘要
目的筛查并分析1996年至2008年我院神经内科所收集的来自全国的24例遗传性痉挛性截瘫(HSP)家系的先证者和32例散发性HSP患者spastin、atlastin、NIPA1和REEP1基因的突变,了解中国人这四个基因的突变特点和基因型-表型关系,为该病的基因诊断奠定基础。进一步对以上患者行MJD基因的筛查研究,明确是否存在MJD的痉挛性截瘫亚型。
方法联合应用变性高效液相色谱分析(DHPLC)和DNA序列分析方法对以上HSP患者的gDNA进行spastin、atlastin和NIPA1基因的突变筛查,并对24例HSP家系的先证者进一步直接测序行以上3个基因的DNA序列分析;另外直接应用测序方法筛查以上全部患者的REEP1基因突变。采用PCR扩增后产物分别进行2%琼脂糖凝胶电泳和变性聚丙烯酰胺凝胶(PAGE)电泳的方法检测上述患者的MJD基因,条带异常的行测序证实。
结果在1个AD-HSP家系中发现1个位于spastin基因上的1616+1g→t杂合突变,是一个新型突变;未发现atlastin基因突变;在1个AD-HSP家系中发现1个位于NIPA1基因上的c.316G＞A杂合突变,是一个已知突变;未发现SPG31基因突变。此外,我们还发现8种spastin基因多态、10种atlastin基因多态、1种NIPA1基因多态,还有5种REEP1基因多态。另外我们发现4个家系存在MJD基因变异,大片段CAG重复数分别为80/28、86/28、83/33和76/29。
结论(1)首次在国内外报道spastin基因上的1616+1g→t杂合突变。
(2)提示atlastin基因型在中国人中可能少见,其突变频率可能存在一定的种族差异。
(3)报道NIPA1基因上的已知杂合突变c.316G＞A,提示为一突变热点;NIPA1基因型在中国人中可能少见,其突变频率与国外报道的基本一致。
(4)首次在国内开展REEP1基因突变分析,提示REEP1基因型在中国人中可能少见,其突变频率可能存在一定的种族差异。
(5)发现了以上4个基因的大量多态,丰富了其多态库;但突变在本组HSP患者中较少见,需要继续筛查HSP的其他基因。
(6) 4例临床诊断HSP的患者通过基因诊断可以确诊为MJD,证实了HSP和SCAs临床表现的复杂性和基因诊断的意义。
(7) DHPLC结合DNA序列分析是一种有效、经济的筛查突变的方法。
Objectives
To detect the mutations of spastin,atlastin,NIPA1 and REEP1 Gene in Chinese patients with hereditary spastic paraplegia(HSP) and establish the base of the gene diagnosis of HSP.To screen the MJD gene changes for the patients above and ascertain the spastic paraplegia subtype of MJD.
Methods
Mutation analysis of spastin,atlastin and NIPA1 gene,carried out by polymerase chain reaction and DHPLC combined with sequencing in 56 unrelated HSP individuals consisting of the indexes from 24 HSP families and 32 sporadic cases.Then spastin, atlastin and NIPA1 genes of these 24 indexes,while REEP1 gene of all 56 individuals were screened by polymerase chain reaction combined with direct sequencing.MJD gene of individuals above were segregated by means of Agrose Gel Electrophoresis as well as Polyacrylamide Gel Electrophoresis after polymerase chain reaction proceeded, and then Changes of them detected were confirmed by sequencing.
Results
One novel mutation of the spastin gene was identified(1616+1g＞t) in one autosomal dominant family;no disease causing mutation of the atlastin gene was detected in all cases;A reported mutation of the NIPA1 gene(c.316G＞A) was identified in an autosomal dominant family;no mutation was identified in REEP1 gene of all cases.8 polymorphisms in the spastin gene,10 polymorphisms in the atlastin gene,1 polymorphism in the NIPA1 gene and 5 polymorphisms in the REEP1 gene were identified.
Conclusions
(1) The mutation of spastin gene,1616+1g→t,have not been reported previously in the world.
(2) The mutation of atlastin gene in Chinese HSP patients may be rare.The lower mutation rate may be correlated with racial diferentation.
(3) We identified c.316G＞A,a mutation of NIPA1 gene in an autosomal dominant HSP family,which is a hotspot.
(4) The REEP1 gene were first screened in Chinese patients,mutations of which may be rare.
(5) We also found a lot of polymorphisms in the four genes.Polymorphisms are common in HSP patients,but mutations are less in the four genes.We should detect other genes of HSP.
(6) We found changes of the MJD gene occure in 4 previously diagnosed HSP families, suggesting the importance of gene screening.
(7) DHPLC together with DNA sequencing is an efficient and economical method for screening mutations.
方法联合应用变性高效液相色谱分析(DHPLC)和DNA序列分析方法对以上HSP患者的gDNA进行spastin、atlastin和NIPA1基因的突变筛查,并对24例HSP家系的先证者进一步直接测序行以上3个基因的DNA序列分析;另外直接应用测序方法筛查以上全部患者的REEP1基因突变。采用PCR扩增后产物分别进行2%琼脂糖凝胶电泳和变性聚丙烯酰胺凝胶(PAGE)电泳的方法检测上述患者的MJD基因,条带异常的行测序证实。
结果在1个AD-HSP家系中发现1个位于spastin基因上的1616+1g→t杂合突变,是一个新型突变;未发现atlastin基因突变;在1个AD-HSP家系中发现1个位于NIPA1基因上的c.316G＞A杂合突变,是一个已知突变;未发现SPG31基因突变。此外,我们还发现8种spastin基因多态、10种atlastin基因多态、1种NIPA1基因多态,还有5种REEP1基因多态。另外我们发现4个家系存在MJD基因变异,大片段CAG重复数分别为80/28、86/28、83/33和76/29。
结论(1)首次在国内外报道spastin基因上的1616+1g→t杂合突变。
(2)提示atlastin基因型在中国人中可能少见,其突变频率可能存在一定的种族差异。
(3)报道NIPA1基因上的已知杂合突变c.316G＞A,提示为一突变热点;NIPA1基因型在中国人中可能少见,其突变频率与国外报道的基本一致。
(4)首次在国内开展REEP1基因突变分析,提示REEP1基因型在中国人中可能少见,其突变频率可能存在一定的种族差异。
(5)发现了以上4个基因的大量多态,丰富了其多态库;但突变在本组HSP患者中较少见,需要继续筛查HSP的其他基因。
(6) 4例临床诊断HSP的患者通过基因诊断可以确诊为MJD,证实了HSP和SCAs临床表现的复杂性和基因诊断的意义。
(7) DHPLC结合DNA序列分析是一种有效、经济的筛查突变的方法。
Objectives
To detect the mutations of spastin,atlastin,NIPA1 and REEP1 Gene in Chinese patients with hereditary spastic paraplegia(HSP) and establish the base of the gene diagnosis of HSP.To screen the MJD gene changes for the patients above and ascertain the spastic paraplegia subtype of MJD.
Methods
Mutation analysis of spastin,atlastin and NIPA1 gene,carried out by polymerase chain reaction and DHPLC combined with sequencing in 56 unrelated HSP individuals consisting of the indexes from 24 HSP families and 32 sporadic cases.Then spastin, atlastin and NIPA1 genes of these 24 indexes,while REEP1 gene of all 56 individuals were screened by polymerase chain reaction combined with direct sequencing.MJD gene of individuals above were segregated by means of Agrose Gel Electrophoresis as well as Polyacrylamide Gel Electrophoresis after polymerase chain reaction proceeded, and then Changes of them detected were confirmed by sequencing.
Results
One novel mutation of the spastin gene was identified(1616+1g＞t) in one autosomal dominant family;no disease causing mutation of the atlastin gene was detected in all cases;A reported mutation of the NIPA1 gene(c.316G＞A) was identified in an autosomal dominant family;no mutation was identified in REEP1 gene of all cases.8 polymorphisms in the spastin gene,10 polymorphisms in the atlastin gene,1 polymorphism in the NIPA1 gene and 5 polymorphisms in the REEP1 gene were identified.
Conclusions
(1) The mutation of spastin gene,1616+1g→t,have not been reported previously in the world.
(2) The mutation of atlastin gene in Chinese HSP patients may be rare.The lower mutation rate may be correlated with racial diferentation.
(3) We identified c.316G＞A,a mutation of NIPA1 gene in an autosomal dominant HSP family,which is a hotspot.
(4) The REEP1 gene were first screened in Chinese patients,mutations of which may be rare.
(5) We also found a lot of polymorphisms in the four genes.Polymorphisms are common in HSP patients,but mutations are less in the four genes.We should detect other genes of HSP.
(6) We found changes of the MJD gene occure in 4 previously diagnosed HSP families, suggesting the importance of gene screening.
(7) DHPLC together with DNA sequencing is an efficient and economical method for screening mutations.
引文
1.Harding AE:Classification of the hereditary ataxias and paraplegias.Lancet 1983;1:1151-1155.
2.吴志英,王柠,林珉婷,慕容慎行.遗传性痉挛性截瘫37例临床研究.新医学,2004,35:30-31.
3.赵坤,吴志英.遗传性痉挛性截瘫新基因位点和功能机制研究的新进展.中华神经科杂志,2008,41
4.Fonknechten N,Mavel D,Byrne P,Davoine CS,Cruaud C,B6nsch D,Samson D,Coutinho P,Hutchinson M,McMonagle P,Burgunder JM,Tartaglione A,Heinzlef O,Feki I,Deufel T,Parfrey N,Brice A,Fontaine B,Prud'homme JF,Weissenbach J,D(u|¨)rr A,Hazan J.Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.Hum Mol Genet,2000,9:637-44
5.Zhao X,Alvarado D,Rainier S,Lemons R,Hedera P,Weber CH,Tukel T,Apak M,Heiman-Patterson T,Ming L,Bui M,Fink JK.Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet,2001,29:326-331
6.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157
7.Reid E,Kloos M,Ashley-Koch A,Hughes L,Bevan S,Svenson IK,Graham FL,Gaskell PC,Dearlove A,Pericak-Vance MA,Rubinsztein DC,Marchuk DA.A kinesin heavy chain(KIF5A)mutation in hereditary spastic paraplegia(SPG 10).Am J Hum Genet,2002,71:1189-1194
8.Hansen J J,D(u|¨)rr A,Coumu-Rebeix 1,Georgopoulos C,Ang D,Nielsen MN,Davoine CS,Brice A,Fontaine B,Gregersen N,Bross P.Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60.Am J Hum Genet,2002,70:1328-1332
9.Z(u|¨)chner S,Wang G,Tran-Viet KN,Nance MA,Gaskell PC,Vance JM,Ashley-Koch AE,Pericak-Vance MA.Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.Am J Hum Genet,2006,79:365-369
10.Valdmanis PN,Meijer IA,Reynolds A,Lei A,MacLeod P,Schlesinger D,Zatz M,Reid E,Dion PA,Drapeau P,Rouleau GA.Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.Am J Hum Genet,2007,80:152-161
11.明蕾,SP63A-遗传性痉挛性截瘫中的不完全外显性和遗传早现.中华医学遗学杂志,2007(24),1:15-18.
12.D(u|¨)rr A,Camuzat A,Colin E,Tallaksen C,Hannequin D,Coutinho P,Fontaine B,Rossi A,Gil R,Rousselle C,Ruberg M,Stevanin G,Brice A.Atlastinl mutations are frequent in young-onset autosomal dominant spastic paraplegia.Arch Neurol,2004,1867-1872.
13.D'Amico A,Tessa A,Sabino A,Bertini E,Santorelli FM,Servidei S.Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.Neurology,2004,2138—2139.
14.Burger J,Metzke H,Paternotte C,Schilling F,Hazan J,Reis A.Autosomal dominant spastic paraplegia with anticipation maps to a 4-cM interval on chromosome 2p21-p24 in a large Germanfamily.Hum Genet,1996,98:371-375.
15.Polo,JM,J.Calleja,O.Combarros,and J.Berciano.Hereditary pure spastic paraplegia:a study of nine families.J.Neurol.Neurosurg.Psychiatry.1993.56:175-181
16.Depienne C,Tallaksen C,Lephay JY,Bricka B,Poea-Guyon S,Fontaine B,Labauge P,Brice A,Durr A.Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.J Med Genet.2006,43(3):259-65.
17.Rainier S,Chai JH,Tokarz D,Nicholls RD,Fink JK.NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia(SPG6).Am J Hum Genet.2003,73:967-971.
18.Chen S,Song C,Guo H,Xu P,Huang W,Zhou Y,Sun J,Li CX,Du Y,Li X,Liu Z,Geng D,Maxwell PH,Zhang C,Wang Y.Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.Hum Mutat.2005,25(2):135-141
19.Reed JA,Wilkinson PA,Patel H,Simpson MA,Chatonnet A,Robay D,Patton MA,Crosby AH,Warner TT.A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.Neurogenetics.2005,6(2):79-84.
20.Munhoz RP,Kawarai T,Teive HA,Raskin S,Sato C,Liang Y,St George-Hyslop PH,Rogaeva E.Clinical and genetic study of a Brazilian family with spastic paraplegia(SPG6 locus).Mov Disord.2006,21(2):279-281.
21.Bien-Willner R,Sambuughin N,Holley H,Bodensteiner J,Sivakumar K.Childhood-onset spastic paraplegia with NIPAL gene mutation.J Child Neurol.2006,21(11):974-977.
22.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics.2007,8(2):155-7.
23.Liu SG,Zhao JJ,Zhuang MY,Li FF,Zhang QJ,Huang SZ,Che FY,Lu DG,Liu SE,Teng JJ,Ma X.Clinical and genetic study of SPG6 mutation in a Chinese family with hereditary spastic paraplegia.J Neurol Sci.2008,266(1-2):109-14.
24.Kaneko S,Kawarai T,Yip E,Salehi-Rad S,Sato C,Orlacchio A,Bemardi G,Liang Y,Hasegawa H,Rogaeva E,St George-Hyslop P.Novel SPG6 Mutation p.A100T in a Japanese Family with Autosomal Dominant Form of Hereditary Spastic Paraplegia.Mov Disord.2006,21(9):1531-3.
25.宋纯,秦炜,陈争,刘焯霖,李洵桦,张成,贺林,王一鸣.一个遗传性痉挛性截瘫家系的致病基因定位研究.中国神经精神疾病杂志.2003,29:424-427.
26.Braschinsky M,Luus SM,Gross-Paju K,Haldre S.The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia.Neuroepidemiology.2009,32(2):89-93.
27.陈嵘,龚黎民,梁秀龄.中国遗传性痉挛性截瘫的临床特点.中风与神经疾病杂志.1998,15:226
28.Hazan J,Fonknechten N,Mavel D,Paternotte C,Samson D,Artiguenave F,Davoine CS,Cruaud C,D(u|¨)rr A,Wincker P,Brottier P,Cattolico L,Barbe V,Burgunder JM,Prud'homme JF,Brice A,Fontaine B,Heilig B,Weissenbach J.Spastin,a new AAA protein,is altered in the most frequent form of autosomal dominant spastic paraplegia.Nature Genetics,1999(23):296-303
29.赵国华,唐北沙,罗巍,严新翔.遗传性痉挛性截瘫的临床和遗传特点.临床神经病学杂志,2003,16(1):31-33
30.Harding AE.The hereditary ataxia and paraplegia.In principle and practice of medical genetics(Vol 1).second ed.Ed by Emery AEH,et al.Churchill Livingstone,1990,383-96.
31.Patrono C,Scarano V,Cricchi F,Melone MA,Chiriaco M,Napolitano A,Malandrini A,De Michele G,Petrozzi L,Giraldi C,Santoro L,Servidei S,Casali C,Filla A,Santorelli FM.Autosomal dominant hereditary spastic paraplegia:DHPLC-based mutation analysis of SPG4reveals eleven novel mutations.Hum Mutat,2005,25:506.
32.Magariello A,Muglia M,Patitucci A,Mazzei R,Conforti FL,Gabriele AL,Sprovieri T,Ungaro C,Gambardella A,Mancuso M,Siciliano G,Branca D,Aguglia U,de Angelis MV,Longo K,Quattrone A.Novel spastin(SPG4) mutations in Italian patients with hereditary spastic paraplegia.Neuromuscul Disord,2006,16:387-390.
33.Evans KJ,Gomes ER,Reisenweber SM,Gundersen GG,Lauring BP.Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing.J Cell Biol,2005,168:599-606
34.White SR,Evans KJ,Lary J,Cole JL,Lauring B.Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing.J Cell Biol,2007,176:995-1005
35.Sanderson CM,Connell JW,Edwards TL,Bright NA,Duley S,Thompson A,Luzio JP,Reid E.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
36.Errico A,Claudiani P,D'Addio M,Rugarli EI.Spastin interacts with the centrosomal protein NA14,and is enriched in the spindle pole,the midbody and the distal axon.Hum Mol Genet,2004,13:2121-2132
37.Reid E,Connell J,Edwards TL,Duley S,Brown SE,Sanderson CM.The hereditary spastic paraplegia protein spastin interacts with the ESCRT-Ⅲ complex-associated endosomal protein CHMP1B.Hum Mol Genet,2005,14:19-38.
38.Mannan AU,Krawen P,Sauter SM,Boehm J,Chronowska A,Paulus W,Neesen J,Engel W.ZFYVE27(SPG33),a novel spastin-binding Protein,is mutated in hereditary spastic paraplegia.Am J Hum Genet,2006,79:351-357
39.Meijer LA,Hand CK,Cossette P,Figlewicz DA,Rouleau GA.Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.Arch Neurol,2002,59:281-286.
40.Sauter S,Miterski B,Klimpe S,Bonsch D,Schols L,Visbeck A,Papke T,Hopf HC,Engel W,Deufel T,Epplen JT,Neesen J.Mutation analysis of the spastin gene(SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia.Hum Mutat,2002,20:127-132.
41.Yabe I,Sasaki H,Tashiro K,Matsuura T,Takegami T,Satoh T.Spastin gene mutation in Japanese with hereditary spastic paraplegia.J Med Genet,2002,39:e46.
42.Proukakis C,Auer-Grumbach M,Wagner K,Wilkinson PA,Reid E,Patton MA,Warner TT,Crosby AH.Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4(Spastin) gene.Hum Mutat,2003,21:170.
43.Patrono C,Scarano V,Cricchi F,Melone MA,Chiriaco M,Napolitano A,Malandrini A,De Michele G,Petrozzi L,Giraldi C,Santoro L,Servidei S,Casali C,Filla A,Santorelli FM.Autosomal dominant hereditary spastic paraplegia:DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.Hum Mutat,2005,25:506.
44.Park SY,Ki CS,Kim HJ,Kim JW,Sung DH,Kim BJ,Lee WY.Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia.Arch Neurol,2005,62:1118-1121.
45.Crippa F,Panzeri C,Martinuzzi A,Arnoldi A,Redaelli F,Tonelli A,Baschirotto C,Vazza G,Mostacciuolo ML,Daga A,Orso G,Profice P,Trabacca A,D'Angelo MG,Comi GP,Galbiati S, Lamperti C,Bonato S,Pandolfo M,Meola G,Musumeci O,Toscano A,Trevisan CP,Bresolin N,Bassi MT.Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.Arch Neurol,2006,63:750-755.
46.Erichsen AK,Inderhaug E,Mattingsdal M,Eiklid K,Tallaksen CM.Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia.Eur J Neurol,2007,14:809-814.
47.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157.
48.赵国华,唐北沙,罗巍,等.中国人遗传性痉挛性截瘫spastin基因突变研究.中华医学遗传学杂志,2003,20:1772-1780.
49.严新翔,赵国华,唐北沙,等.遗传性痉挛性截瘫spastin、atlastin和paraplegin基因突变分析.中华神经科杂志,2005,38:683-685.
50.唐北沙,赵国华,陈昕,等.遗传性痉挛性截瘫一家系的临床特点与spastin基因突变分析.中华神经科杂志,2005,38:38-41.
51.Hazan J,Lamy C,Melki J,Munnich A,de Recondo J,Weissenbach J.Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q.Nat Genet.1993,5(2):163-7.
52.Zhu PP,Patterson A,Lavoie B,Stadler J,Shoeb M,Patel R,Blackstone C.Cellular Localization,Oligomerization,and Membrane Association of the Hereditary Spastic Paraplegia 3A(SPG3A)Protein Atlastin.J Biol Chem.2003,278(49):49063-71.
53.Namekawa M,Muriel MP,Janer A,Latouche M,Dauphin A,Debeir T,Martin E,Duyckaerts C,Prigent A,Depienne C,Sittler A,Brice A,Ruberg M.Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis.Mol Cell Neurosci.2007,35(1):1-13.
54.Sauter SM,Engel W,Neumann LM,Kunze J,Neesen J.Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of liSP linked to the SPG3A locus.Hum Mutat.2004,23(1):98
55.Sanderson CM,Connell JW,Edwards TL,Bright NA,Duley S,Thompson A,Luzio JP,Reid E.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
56.Evans K,Keller C,Pavur K,Glasgow K,Conn B,Lauring B.Interaction of two hereditary spastic paraplegia gene products,spastin and atlastin,suggests a common pathway for axonal maintenance.Proc Natl Acad Sci USA.2006,103(28):10666-71.
57.Muglia M,Magariello A,Nicoletti G,Patitucci A,Gabriele AL,Conforti FL,Mazzei R,Camcciolo M,Ardito B,Lastilla M,Tedeschi G,Quattrone A.Further evidence that SPG3A gene Mutations cause autosomal dominant hereditary spastic paraplegia.Ann Neurol,2002,51(6):794-795
58.Tessa A,Casali C,Damiano M,Bruno C,Fortini D,Patrono C,Cricchi F,Valoppi M,Nappi G,Amabile GA,Bertini E,Santorelli FM.SPG3A:An additional family carrying a new atlastin mutation.Neurology,2002,59(12):2002-2005
59.Wilkinson PA,Hart PE,Patel H,Warner TT,Crosby AH.SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia.J Neurol Sci,2003,216(1):43-45
60.Sauter SM,Engel W,Neumann LM,Kunze J,Neesen J.Novel mutations in the atlastin gene(SPG3A)in families with autosomal dominant heerditary spastic paraplegia and evidence for late onset forms of liSP linked to the SPG3A locus.Hum Mutat,2004,23(1):98-103
61.陈昕,唐北沙,赵国华等.遗传性痉挛性截瘫atlastin基因突变分析.临床神经病学杂志,2005,18:330-331.
62.陈素琴,周雁,李洵桦,等.SPG3A基因的一个新突变导致重症遗传性痉挛性截瘫.科学通报,2006,51:1854-1856.
63.Goytain A,Hines RM,E1-Husseini A,Quamme GA.NIPA1(SPG6),the basis for autosomal dominant form of hereditary spastic paraplegia,encodes a functional Mg~(2+) transporter.J Biol Chem,2007,282:8060-8068
64.Saito H,Kubota M,Roberts RW,Chi Q,Matsunami H.RTP family members induce functional expression of mammalian odorant receptors.Cell,2004,119:679-691
65.Beetz C,Schiile R,Deconinck T,Tran-Viet KN,Zhu H,Kremer BP,Frints SG,van Zelst-Stams WA,Byrne P,Otto S,Nygren AO,Baets J,Smets K,Ceulemans B,Dan B,Nagan N,Kassubek J,Klimpe S,Klopstock T,Stolze H,Smeets HJ,Schrander-Stumpel CT,Hutchinson M,van de Warrenburg BP,Braastad C,Deufel T,Pericak-Vance M,Sch61s L,de Jonghe P,Z(u|¨)chner S.REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.Brain.2008,131(Pt4):1078-86.
66.Liu SG,Che FY,Heng XY,Li FF,Huang SZ,Lu de G,Hou S J,Liu SE,Wang Q,Wang HP,Ma X.Clinical and genetic study of a novel mutation in the REEP1 gene.Synapse.2009,63(3):201-5
67.Schlang KJ,Aming L,Epplen JT,Stemmler S.Autosomal dominant hereditary spastic paraplegia:novel mutations in the REEP1 gene(SPG31).BMC Med Genet.2008,21;9:71
68.Erichsen AK,Koht J,Stray-Pedersen A,Abdelnoor M,Tallaksen CM.Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway:a population-based study.Brain.2009,132:1577-88.
69.Nielsen JE,Johnsen B,Koefoed P,Scheuer KH,Granbech-Jensen M,Law I,Krabbe K,N0rrem0lle A,Eiberg H,Sendergard H,Dam M,Rehfeld JF,Krarup C,Paulson OB,Hasholt L,Sorensen SA.Hereditary spastic paraplegia with cerebellar ataxia:a complex phenotype associated with a new SPG4 gene mutation.Eur J Neurol.2004,11(12):817-24.
70.Klebe S,Azzedine H,Durr A,Bastien P,Bouslam N,Elleuch N,Forlani S,Charon C,Koenig M,Melki J,Brice A,Stevanin G.Autosomal recessive spastic paraplegia(SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.Brain.2006,129(Pt 6):1456-62.
71.Takiyama Y,Oyanagi S,Kawashima S,Sakamoto H,Saito K,Yoshida M,Tsuji S,Mizuno Y,Nishizawa M.A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q.Neurology,1994.44,1302-1308.
72.Sakai T,Kawakami H.Machado-Joseph disease:A proposal of spastic paraplegic subtype.Neurology 1996;46:846-847.
73.Kaneko A,Narabayashi Y,Itokawa K,Nakazato Y,Hosokawa T,Iwasaki S,Ohno R,Hamaguchi K,flceda M,Nomura M.A case of Machado-Joseph disease presenting with spastic paraparesis.J Neurol Neurosurg Psychiatry 1997;62:542-543.
74.Teive HA,Iwamoto FM,Camargo CH,Lopes-Cendes I,Werneck LC.Machado-Joseph disease versus hereditary spastic paraplegia.Arq Neuropsiquiatr 2001;59:809-811.
75.Kawaguchi Y,Okamoto T,Taniwaki M,Aizawa M,Inoue M,Katayama S,Kawakami H,Nakamura S,Nishimura M,Akiguchi I,et al.CAG expansions in a novel gene for Machado-Joseeph disease at chromosome 14q32.1.Nature Genet,1994.8,221-228.
76.Sequeiros J,Coutinho P.Epidemiology and clinical aspects of Machado-Joseph disease.Adv Neurol,61,139-153.
77.Maciel P,Gaspar C,DeStefano AL,et al.Correlation between CAG repeat length and clinical features in Machado-Joseph disease.Am J Hum Genet,1995,57:54-61.
1.吴志英,王柠,林珉婷,慕容慎行.遗传性痉挛性截瘫37例临床研究.新医学,2004,35:30-31
2.陈昕,赵国华,唐北沙.遗传性痉挛性截瘫的病理、遗传学、发病机制和临床的研究进展.床神经病学杂,2006,19:70-72
3.Fonknechten N,Mavel D,Byrne P,et al.Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.Hum Mol Genet,2000,9:637-44
4.Zhao X,Alvarado D,Rainier S,et al.Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet,2001,29:326-331
5.Klebe S,Lacour A,Durr A,et al.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157
6.Reid E,Kloos M,Ashley-Koch A,et al.A kinesin heavy chain(KIF5A) mutation in hereditary spastic paraplegia(SPG10).Am J Hum Genet,2002,71:1189-1194
7.Hansen JJ,Durr A,Coumu-Rebeix I,et al.Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60.Am J Hum Genet,2002,70:1328-1332
8.Valdmanis PN,Meijer IA,Reynolds A,et al.Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.Am J Hum Genet,2007,80:152-161
9.Zuchner S,Wang G,Tran-Viet K-N,et al.Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.Am J Hum Genet,2006,79:365-369
10.Salinas S,Carazo-Salas RE,Proukakis C,et al.Human spastin has multiple microtubule-related functions.J Neurochem,2005,95:1411-1420
11.Evans KJ,Gomes ER,Reisenweber SM,et al.Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing.J Cell Biol,2005,168:599-606
12.White SR,Evans KJ,Lary J,et al.Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing.J Cell Biol,2007,176:995-1005
13.Molon A,Giovanni SD,Chen YW,et al.Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle.Neurology,2004,62:1097-1104
14.Errico A,Claudiani P,D'Addio M,et al.Spastin interacts with the centrosomal protein NA14,and is enriched in the spindle pole,the midbody and the distal axon.Hum Mol Genet,2004,13:2121-2132
15.Reid E,Connell J,Edwards TL,et al.The hereditary spastic paraplegia protein spastin interacts with the ESCRT-Ⅲ complex-associated endosomal protein CHMPlB.Hum Mol Genet,2005,14:19-38.
16.Sanderson CM,Connell JW,Edwards TL,et al.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
17.Mannan AU,Krawen P,Sauter SM,et al.ZFYVE27(SPG33),a novel spastin-binding Protein,is mutated in hereditary spastic paraplegia.Am J Hum Genet,2006,79:351-357
18.赵国华,唐北沙．遗传性痉挛性截瘫的分子遗传学进展．中华神经科杂志,2003,36：152-154
19.Evans K,Keller C,Pavur K,et al.Interaction of two hereditary spastic paraplegia gene products,spastin and atlastin,suggests a common pathway for axonal maintenance.Proc Natl Acad Sci USA,2006,103:10666-10671
20.Namekawa M,Muriela MP,Janer A,et al.Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis.Mol Cell Neurosci,2007,35:1-13
21.Rainier S,Chai J-H,Tokarz D,et al.NIPAl Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia(SPG6).Am J Hum Genet,2003,73:967-971
22.Chen S,Song C,Guo H,et al.Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.Hum Mut,2005,25:135-141
23.Reed JA,Wilkinson PA,Patel H,et al.A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.Neurogenetics,2005,6:79-84
24.Goytain A,Hines RM,El-Husseini A,Quamme GA.NIPA1(SPG6),the basis for autosomal dominant form of hereditary spastic paraplegia,encodes a functional Mg2+ transporter.J Biol Chem,2007,282:8060-8068
25.Windpassinger C,Auer-Grumbach M,Irobi J,et al.Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.Nat Genet,2004,36:271-276.
26.Saito H,Kubota M,Roberts RW,et al.RTP family members induce functional expression of mammalian odorant receptors.Cell,2004,119:679-691
27.Atorino L,Silvestri L,Koppen M,et al.Loss of m-AAA protease in mitochondria causes complex Ⅰ deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.J Cell Biol,2003,163:777-787
28.Bakowska JC,Jenkins R,Pendleton J,Blackstone C.The Troyer syndrome(SPG20) protein spartin interacts with Eps15.Biochem Biophys Res Commun,2005,334:1042-1048
29.Lu J,Rashid F,Byrne PC.The hereditary spastic paraplegia protein spartin localises to mitochondria.J Neurochem,2006,98:1908-1919
30.Robay D,Patel H,Simpson MA,et al.Endogenous spartin,mutated in hereditary spastic paraplegia,has a complex subcellular localization suggesting diverse roles in neurons.Exp Cell Res,2006,312:2764-2777
31.Bakowska JC,Jupille H,Fatheddin P,et al.Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking.Mol Biol Cell,2007,18:1683-1692.
32.Stevanin G,Santorelli FM,Azzedine H,et al.Mutations in SPGll,encoding spatacsin,are a major cause of spastic paraplegia with thin corpus callosum.Nat Genet,2007,39:366-372
33.Edgar JM,McLaughlin M,Yool D,et al.Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.J Cell Biol,2004,166:121-131
2.吴志英,王柠,林珉婷,慕容慎行.遗传性痉挛性截瘫37例临床研究.新医学,2004,35:30-31.
3.赵坤,吴志英.遗传性痉挛性截瘫新基因位点和功能机制研究的新进展.中华神经科杂志,2008,41
4.Fonknechten N,Mavel D,Byrne P,Davoine CS,Cruaud C,B6nsch D,Samson D,Coutinho P,Hutchinson M,McMonagle P,Burgunder JM,Tartaglione A,Heinzlef O,Feki I,Deufel T,Parfrey N,Brice A,Fontaine B,Prud'homme JF,Weissenbach J,D(u|¨)rr A,Hazan J.Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.Hum Mol Genet,2000,9:637-44
5.Zhao X,Alvarado D,Rainier S,Lemons R,Hedera P,Weber CH,Tukel T,Apak M,Heiman-Patterson T,Ming L,Bui M,Fink JK.Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet,2001,29:326-331
6.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157
7.Reid E,Kloos M,Ashley-Koch A,Hughes L,Bevan S,Svenson IK,Graham FL,Gaskell PC,Dearlove A,Pericak-Vance MA,Rubinsztein DC,Marchuk DA.A kinesin heavy chain(KIF5A)mutation in hereditary spastic paraplegia(SPG 10).Am J Hum Genet,2002,71:1189-1194
8.Hansen J J,D(u|¨)rr A,Coumu-Rebeix 1,Georgopoulos C,Ang D,Nielsen MN,Davoine CS,Brice A,Fontaine B,Gregersen N,Bross P.Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60.Am J Hum Genet,2002,70:1328-1332
9.Z(u|¨)chner S,Wang G,Tran-Viet KN,Nance MA,Gaskell PC,Vance JM,Ashley-Koch AE,Pericak-Vance MA.Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.Am J Hum Genet,2006,79:365-369
10.Valdmanis PN,Meijer IA,Reynolds A,Lei A,MacLeod P,Schlesinger D,Zatz M,Reid E,Dion PA,Drapeau P,Rouleau GA.Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.Am J Hum Genet,2007,80:152-161
11.明蕾,SP63A-遗传性痉挛性截瘫中的不完全外显性和遗传早现.中华医学遗学杂志,2007(24),1:15-18.
12.D(u|¨)rr A,Camuzat A,Colin E,Tallaksen C,Hannequin D,Coutinho P,Fontaine B,Rossi A,Gil R,Rousselle C,Ruberg M,Stevanin G,Brice A.Atlastinl mutations are frequent in young-onset autosomal dominant spastic paraplegia.Arch Neurol,2004,1867-1872.
13.D'Amico A,Tessa A,Sabino A,Bertini E,Santorelli FM,Servidei S.Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene.Neurology,2004,2138—2139.
14.Burger J,Metzke H,Paternotte C,Schilling F,Hazan J,Reis A.Autosomal dominant spastic paraplegia with anticipation maps to a 4-cM interval on chromosome 2p21-p24 in a large Germanfamily.Hum Genet,1996,98:371-375.
15.Polo,JM,J.Calleja,O.Combarros,and J.Berciano.Hereditary pure spastic paraplegia:a study of nine families.J.Neurol.Neurosurg.Psychiatry.1993.56:175-181
16.Depienne C,Tallaksen C,Lephay JY,Bricka B,Poea-Guyon S,Fontaine B,Labauge P,Brice A,Durr A.Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.J Med Genet.2006,43(3):259-65.
17.Rainier S,Chai JH,Tokarz D,Nicholls RD,Fink JK.NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia(SPG6).Am J Hum Genet.2003,73:967-971.
18.Chen S,Song C,Guo H,Xu P,Huang W,Zhou Y,Sun J,Li CX,Du Y,Li X,Liu Z,Geng D,Maxwell PH,Zhang C,Wang Y.Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.Hum Mutat.2005,25(2):135-141
19.Reed JA,Wilkinson PA,Patel H,Simpson MA,Chatonnet A,Robay D,Patton MA,Crosby AH,Warner TT.A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.Neurogenetics.2005,6(2):79-84.
20.Munhoz RP,Kawarai T,Teive HA,Raskin S,Sato C,Liang Y,St George-Hyslop PH,Rogaeva E.Clinical and genetic study of a Brazilian family with spastic paraplegia(SPG6 locus).Mov Disord.2006,21(2):279-281.
21.Bien-Willner R,Sambuughin N,Holley H,Bodensteiner J,Sivakumar K.Childhood-onset spastic paraplegia with NIPAL gene mutation.J Child Neurol.2006,21(11):974-977.
22.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics.2007,8(2):155-7.
23.Liu SG,Zhao JJ,Zhuang MY,Li FF,Zhang QJ,Huang SZ,Che FY,Lu DG,Liu SE,Teng JJ,Ma X.Clinical and genetic study of SPG6 mutation in a Chinese family with hereditary spastic paraplegia.J Neurol Sci.2008,266(1-2):109-14.
24.Kaneko S,Kawarai T,Yip E,Salehi-Rad S,Sato C,Orlacchio A,Bemardi G,Liang Y,Hasegawa H,Rogaeva E,St George-Hyslop P.Novel SPG6 Mutation p.A100T in a Japanese Family with Autosomal Dominant Form of Hereditary Spastic Paraplegia.Mov Disord.2006,21(9):1531-3.
25.宋纯,秦炜,陈争,刘焯霖,李洵桦,张成,贺林,王一鸣.一个遗传性痉挛性截瘫家系的致病基因定位研究.中国神经精神疾病杂志.2003,29:424-427.
26.Braschinsky M,Luus SM,Gross-Paju K,Haldre S.The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia.Neuroepidemiology.2009,32(2):89-93.
27.陈嵘,龚黎民,梁秀龄.中国遗传性痉挛性截瘫的临床特点.中风与神经疾病杂志.1998,15:226
28.Hazan J,Fonknechten N,Mavel D,Paternotte C,Samson D,Artiguenave F,Davoine CS,Cruaud C,D(u|¨)rr A,Wincker P,Brottier P,Cattolico L,Barbe V,Burgunder JM,Prud'homme JF,Brice A,Fontaine B,Heilig B,Weissenbach J.Spastin,a new AAA protein,is altered in the most frequent form of autosomal dominant spastic paraplegia.Nature Genetics,1999(23):296-303
29.赵国华,唐北沙,罗巍,严新翔.遗传性痉挛性截瘫的临床和遗传特点.临床神经病学杂志,2003,16(1):31-33
30.Harding AE.The hereditary ataxia and paraplegia.In principle and practice of medical genetics(Vol 1).second ed.Ed by Emery AEH,et al.Churchill Livingstone,1990,383-96.
31.Patrono C,Scarano V,Cricchi F,Melone MA,Chiriaco M,Napolitano A,Malandrini A,De Michele G,Petrozzi L,Giraldi C,Santoro L,Servidei S,Casali C,Filla A,Santorelli FM.Autosomal dominant hereditary spastic paraplegia:DHPLC-based mutation analysis of SPG4reveals eleven novel mutations.Hum Mutat,2005,25:506.
32.Magariello A,Muglia M,Patitucci A,Mazzei R,Conforti FL,Gabriele AL,Sprovieri T,Ungaro C,Gambardella A,Mancuso M,Siciliano G,Branca D,Aguglia U,de Angelis MV,Longo K,Quattrone A.Novel spastin(SPG4) mutations in Italian patients with hereditary spastic paraplegia.Neuromuscul Disord,2006,16:387-390.
33.Evans KJ,Gomes ER,Reisenweber SM,Gundersen GG,Lauring BP.Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing.J Cell Biol,2005,168:599-606
34.White SR,Evans KJ,Lary J,Cole JL,Lauring B.Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing.J Cell Biol,2007,176:995-1005
35.Sanderson CM,Connell JW,Edwards TL,Bright NA,Duley S,Thompson A,Luzio JP,Reid E.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
36.Errico A,Claudiani P,D'Addio M,Rugarli EI.Spastin interacts with the centrosomal protein NA14,and is enriched in the spindle pole,the midbody and the distal axon.Hum Mol Genet,2004,13:2121-2132
37.Reid E,Connell J,Edwards TL,Duley S,Brown SE,Sanderson CM.The hereditary spastic paraplegia protein spastin interacts with the ESCRT-Ⅲ complex-associated endosomal protein CHMP1B.Hum Mol Genet,2005,14:19-38.
38.Mannan AU,Krawen P,Sauter SM,Boehm J,Chronowska A,Paulus W,Neesen J,Engel W.ZFYVE27(SPG33),a novel spastin-binding Protein,is mutated in hereditary spastic paraplegia.Am J Hum Genet,2006,79:351-357
39.Meijer LA,Hand CK,Cossette P,Figlewicz DA,Rouleau GA.Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.Arch Neurol,2002,59:281-286.
40.Sauter S,Miterski B,Klimpe S,Bonsch D,Schols L,Visbeck A,Papke T,Hopf HC,Engel W,Deufel T,Epplen JT,Neesen J.Mutation analysis of the spastin gene(SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia.Hum Mutat,2002,20:127-132.
41.Yabe I,Sasaki H,Tashiro K,Matsuura T,Takegami T,Satoh T.Spastin gene mutation in Japanese with hereditary spastic paraplegia.J Med Genet,2002,39:e46.
42.Proukakis C,Auer-Grumbach M,Wagner K,Wilkinson PA,Reid E,Patton MA,Warner TT,Crosby AH.Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4(Spastin) gene.Hum Mutat,2003,21:170.
43.Patrono C,Scarano V,Cricchi F,Melone MA,Chiriaco M,Napolitano A,Malandrini A,De Michele G,Petrozzi L,Giraldi C,Santoro L,Servidei S,Casali C,Filla A,Santorelli FM.Autosomal dominant hereditary spastic paraplegia:DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.Hum Mutat,2005,25:506.
44.Park SY,Ki CS,Kim HJ,Kim JW,Sung DH,Kim BJ,Lee WY.Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia.Arch Neurol,2005,62:1118-1121.
45.Crippa F,Panzeri C,Martinuzzi A,Arnoldi A,Redaelli F,Tonelli A,Baschirotto C,Vazza G,Mostacciuolo ML,Daga A,Orso G,Profice P,Trabacca A,D'Angelo MG,Comi GP,Galbiati S, Lamperti C,Bonato S,Pandolfo M,Meola G,Musumeci O,Toscano A,Trevisan CP,Bresolin N,Bassi MT.Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia.Arch Neurol,2006,63:750-755.
46.Erichsen AK,Inderhaug E,Mattingsdal M,Eiklid K,Tallaksen CM.Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia.Eur J Neurol,2007,14:809-814.
47.Klebe S,Lacour A,Durr A,Stojkovic T,Depienne C,Forlani S,Poea-Guyon S,Vuillaume I,Sablonniere B,Vermersch P,Brice A,Stevanin G.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157.
48.赵国华,唐北沙,罗巍,等.中国人遗传性痉挛性截瘫spastin基因突变研究.中华医学遗传学杂志,2003,20:1772-1780.
49.严新翔,赵国华,唐北沙,等.遗传性痉挛性截瘫spastin、atlastin和paraplegin基因突变分析.中华神经科杂志,2005,38:683-685.
50.唐北沙,赵国华,陈昕,等.遗传性痉挛性截瘫一家系的临床特点与spastin基因突变分析.中华神经科杂志,2005,38:38-41.
51.Hazan J,Lamy C,Melki J,Munnich A,de Recondo J,Weissenbach J.Autosomal dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to chromosome 14q.Nat Genet.1993,5(2):163-7.
52.Zhu PP,Patterson A,Lavoie B,Stadler J,Shoeb M,Patel R,Blackstone C.Cellular Localization,Oligomerization,and Membrane Association of the Hereditary Spastic Paraplegia 3A(SPG3A)Protein Atlastin.J Biol Chem.2003,278(49):49063-71.
53.Namekawa M,Muriel MP,Janer A,Latouche M,Dauphin A,Debeir T,Martin E,Duyckaerts C,Prigent A,Depienne C,Sittler A,Brice A,Ruberg M.Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis.Mol Cell Neurosci.2007,35(1):1-13.
54.Sauter SM,Engel W,Neumann LM,Kunze J,Neesen J.Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of liSP linked to the SPG3A locus.Hum Mutat.2004,23(1):98
55.Sanderson CM,Connell JW,Edwards TL,Bright NA,Duley S,Thompson A,Luzio JP,Reid E.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
56.Evans K,Keller C,Pavur K,Glasgow K,Conn B,Lauring B.Interaction of two hereditary spastic paraplegia gene products,spastin and atlastin,suggests a common pathway for axonal maintenance.Proc Natl Acad Sci USA.2006,103(28):10666-71.
57.Muglia M,Magariello A,Nicoletti G,Patitucci A,Gabriele AL,Conforti FL,Mazzei R,Camcciolo M,Ardito B,Lastilla M,Tedeschi G,Quattrone A.Further evidence that SPG3A gene Mutations cause autosomal dominant hereditary spastic paraplegia.Ann Neurol,2002,51(6):794-795
58.Tessa A,Casali C,Damiano M,Bruno C,Fortini D,Patrono C,Cricchi F,Valoppi M,Nappi G,Amabile GA,Bertini E,Santorelli FM.SPG3A:An additional family carrying a new atlastin mutation.Neurology,2002,59(12):2002-2005
59.Wilkinson PA,Hart PE,Patel H,Warner TT,Crosby AH.SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia.J Neurol Sci,2003,216(1):43-45
60.Sauter SM,Engel W,Neumann LM,Kunze J,Neesen J.Novel mutations in the atlastin gene(SPG3A)in families with autosomal dominant heerditary spastic paraplegia and evidence for late onset forms of liSP linked to the SPG3A locus.Hum Mutat,2004,23(1):98-103
61.陈昕,唐北沙,赵国华等.遗传性痉挛性截瘫atlastin基因突变分析.临床神经病学杂志,2005,18:330-331.
62.陈素琴,周雁,李洵桦,等.SPG3A基因的一个新突变导致重症遗传性痉挛性截瘫.科学通报,2006,51:1854-1856.
63.Goytain A,Hines RM,E1-Husseini A,Quamme GA.NIPA1(SPG6),the basis for autosomal dominant form of hereditary spastic paraplegia,encodes a functional Mg~(2+) transporter.J Biol Chem,2007,282:8060-8068
64.Saito H,Kubota M,Roberts RW,Chi Q,Matsunami H.RTP family members induce functional expression of mammalian odorant receptors.Cell,2004,119:679-691
65.Beetz C,Schiile R,Deconinck T,Tran-Viet KN,Zhu H,Kremer BP,Frints SG,van Zelst-Stams WA,Byrne P,Otto S,Nygren AO,Baets J,Smets K,Ceulemans B,Dan B,Nagan N,Kassubek J,Klimpe S,Klopstock T,Stolze H,Smeets HJ,Schrander-Stumpel CT,Hutchinson M,van de Warrenburg BP,Braastad C,Deufel T,Pericak-Vance M,Sch61s L,de Jonghe P,Z(u|¨)chner S.REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.Brain.2008,131(Pt4):1078-86.
66.Liu SG,Che FY,Heng XY,Li FF,Huang SZ,Lu de G,Hou S J,Liu SE,Wang Q,Wang HP,Ma X.Clinical and genetic study of a novel mutation in the REEP1 gene.Synapse.2009,63(3):201-5
67.Schlang KJ,Aming L,Epplen JT,Stemmler S.Autosomal dominant hereditary spastic paraplegia:novel mutations in the REEP1 gene(SPG31).BMC Med Genet.2008,21;9:71
68.Erichsen AK,Koht J,Stray-Pedersen A,Abdelnoor M,Tallaksen CM.Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway:a population-based study.Brain.2009,132:1577-88.
69.Nielsen JE,Johnsen B,Koefoed P,Scheuer KH,Granbech-Jensen M,Law I,Krabbe K,N0rrem0lle A,Eiberg H,Sendergard H,Dam M,Rehfeld JF,Krarup C,Paulson OB,Hasholt L,Sorensen SA.Hereditary spastic paraplegia with cerebellar ataxia:a complex phenotype associated with a new SPG4 gene mutation.Eur J Neurol.2004,11(12):817-24.
70.Klebe S,Azzedine H,Durr A,Bastien P,Bouslam N,Elleuch N,Forlani S,Charon C,Koenig M,Melki J,Brice A,Stevanin G.Autosomal recessive spastic paraplegia(SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.Brain.2006,129(Pt 6):1456-62.
71.Takiyama Y,Oyanagi S,Kawashima S,Sakamoto H,Saito K,Yoshida M,Tsuji S,Mizuno Y,Nishizawa M.A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q.Neurology,1994.44,1302-1308.
72.Sakai T,Kawakami H.Machado-Joseph disease:A proposal of spastic paraplegic subtype.Neurology 1996;46:846-847.
73.Kaneko A,Narabayashi Y,Itokawa K,Nakazato Y,Hosokawa T,Iwasaki S,Ohno R,Hamaguchi K,flceda M,Nomura M.A case of Machado-Joseph disease presenting with spastic paraparesis.J Neurol Neurosurg Psychiatry 1997;62:542-543.
74.Teive HA,Iwamoto FM,Camargo CH,Lopes-Cendes I,Werneck LC.Machado-Joseph disease versus hereditary spastic paraplegia.Arq Neuropsiquiatr 2001;59:809-811.
75.Kawaguchi Y,Okamoto T,Taniwaki M,Aizawa M,Inoue M,Katayama S,Kawakami H,Nakamura S,Nishimura M,Akiguchi I,et al.CAG expansions in a novel gene for Machado-Joseeph disease at chromosome 14q32.1.Nature Genet,1994.8,221-228.
76.Sequeiros J,Coutinho P.Epidemiology and clinical aspects of Machado-Joseph disease.Adv Neurol,61,139-153.
77.Maciel P,Gaspar C,DeStefano AL,et al.Correlation between CAG repeat length and clinical features in Machado-Joseph disease.Am J Hum Genet,1995,57:54-61.
1.吴志英,王柠,林珉婷,慕容慎行.遗传性痉挛性截瘫37例临床研究.新医学,2004,35:30-31
2.陈昕,赵国华,唐北沙.遗传性痉挛性截瘫的病理、遗传学、发病机制和临床的研究进展.床神经病学杂,2006,19:70-72
3.Fonknechten N,Mavel D,Byrne P,et al.Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.Hum Mol Genet,2000,9:637-44
4.Zhao X,Alvarado D,Rainier S,et al.Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet,2001,29:326-331
5.Klebe S,Lacour A,Durr A,et al.NIPA1(SPG6) mutations are a rare cause of autosomal dominant spastic paraplegia in Europe.Neurogenetics,2007,8:155-157
6.Reid E,Kloos M,Ashley-Koch A,et al.A kinesin heavy chain(KIF5A) mutation in hereditary spastic paraplegia(SPG10).Am J Hum Genet,2002,71:1189-1194
7.Hansen JJ,Durr A,Coumu-Rebeix I,et al.Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60.Am J Hum Genet,2002,70:1328-1332
8.Valdmanis PN,Meijer IA,Reynolds A,et al.Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.Am J Hum Genet,2007,80:152-161
9.Zuchner S,Wang G,Tran-Viet K-N,et al.Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.Am J Hum Genet,2006,79:365-369
10.Salinas S,Carazo-Salas RE,Proukakis C,et al.Human spastin has multiple microtubule-related functions.J Neurochem,2005,95:1411-1420
11.Evans KJ,Gomes ER,Reisenweber SM,et al.Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing.J Cell Biol,2005,168:599-606
12.White SR,Evans KJ,Lary J,et al.Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing.J Cell Biol,2007,176:995-1005
13.Molon A,Giovanni SD,Chen YW,et al.Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle.Neurology,2004,62:1097-1104
14.Errico A,Claudiani P,D'Addio M,et al.Spastin interacts with the centrosomal protein NA14,and is enriched in the spindle pole,the midbody and the distal axon.Hum Mol Genet,2004,13:2121-2132
15.Reid E,Connell J,Edwards TL,et al.The hereditary spastic paraplegia protein spastin interacts with the ESCRT-Ⅲ complex-associated endosomal protein CHMPlB.Hum Mol Genet,2005,14:19-38.
16.Sanderson CM,Connell JW,Edwards TL,et al.Spastin and atlastin,two proteins mutated in autosomal-dominant hereditary spastic paraplegia,are binding partners.Hum Mol Genet,2006,15:307-318
17.Mannan AU,Krawen P,Sauter SM,et al.ZFYVE27(SPG33),a novel spastin-binding Protein,is mutated in hereditary spastic paraplegia.Am J Hum Genet,2006,79:351-357
18.赵国华,唐北沙．遗传性痉挛性截瘫的分子遗传学进展．中华神经科杂志,2003,36：152-154
19.Evans K,Keller C,Pavur K,et al.Interaction of two hereditary spastic paraplegia gene products,spastin and atlastin,suggests a common pathway for axonal maintenance.Proc Natl Acad Sci USA,2006,103:10666-10671
20.Namekawa M,Muriela MP,Janer A,et al.Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis.Mol Cell Neurosci,2007,35:1-13
21.Rainier S,Chai J-H,Tokarz D,et al.NIPAl Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia(SPG6).Am J Hum Genet,2003,73:967-971
22.Chen S,Song C,Guo H,et al.Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families.Hum Mut,2005,25:135-141
23.Reed JA,Wilkinson PA,Patel H,et al.A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.Neurogenetics,2005,6:79-84
24.Goytain A,Hines RM,El-Husseini A,Quamme GA.NIPA1(SPG6),the basis for autosomal dominant form of hereditary spastic paraplegia,encodes a functional Mg2+ transporter.J Biol Chem,2007,282:8060-8068
25.Windpassinger C,Auer-Grumbach M,Irobi J,et al.Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.Nat Genet,2004,36:271-276.
26.Saito H,Kubota M,Roberts RW,et al.RTP family members induce functional expression of mammalian odorant receptors.Cell,2004,119:679-691
27.Atorino L,Silvestri L,Koppen M,et al.Loss of m-AAA protease in mitochondria causes complex Ⅰ deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.J Cell Biol,2003,163:777-787
28.Bakowska JC,Jenkins R,Pendleton J,Blackstone C.The Troyer syndrome(SPG20) protein spartin interacts with Eps15.Biochem Biophys Res Commun,2005,334:1042-1048
29.Lu J,Rashid F,Byrne PC.The hereditary spastic paraplegia protein spartin localises to mitochondria.J Neurochem,2006,98:1908-1919
30.Robay D,Patel H,Simpson MA,et al.Endogenous spartin,mutated in hereditary spastic paraplegia,has a complex subcellular localization suggesting diverse roles in neurons.Exp Cell Res,2006,312:2764-2777
31.Bakowska JC,Jupille H,Fatheddin P,et al.Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking.Mol Biol Cell,2007,18:1683-1692.
32.Stevanin G,Santorelli FM,Azzedine H,et al.Mutations in SPGll,encoding spatacsin,are a major cause of spastic paraplegia with thin corpus callosum.Nat Genet,2007,39:366-372
33.Edgar JM,McLaughlin M,Yool D,et al.Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.J Cell Biol,2004,166:121-131