贵州少数民族遗传性痉挛性截瘫患者spastin基因突变的研究

目的 研究贵州地区少数民族遗传性痉挛性截瘫(HSP)患者spastin基因突变的特征.方法 应用PCR产物直接DNA测序法,对贵州16例少数民族(布依、苗、彝族)HSP患者(其中14例患者来自3个常染色体显性遗传家系,2例散发患者)spastin基因的8、10、14号外显子进行分析.将测序结果与人类基因组SPG4基因序列进行比对.结果 16例患者的spastin基因8、10、14号外显子直接DNA测序结果均未发现有突变.结论 贵州少数民族HSP患者spastin基因8、10、14号外显子的突变可能较少见,其与汉族HSP患者的spastin基因突变形式可能不同.     

遗传性痉挛性截瘫2家系的临床特点与spastin基因突变分析

目的:探讨2个家系遗传3代以上常染色体显性遗传性痉挛性截瘫(AD-HSP)的临床特点及其与spastin基因突变的关系。方法:对2个AD-HSP家系进行详细的临床检查,总结所有患者临床特点,并应用PCR技术结合DNA序列分析方法,检测2家系先证者spastin基因的突变情况。结果:2家系中所有患者均具有HSP的典型表现,PCR-DNA序列分析2例先证者spastin基因的17个外显子均未发现有异常突变。结论:2家系HSP患者具有典型的AD-HSP临床表现,并非spastin基因外显子突变所致。     

遗传性痉挛性截瘫一家系的临床特点与spastin基因突变分析

目的　探讨常染色体显性遗传的遗传性痉挛性截瘫 (SPG)一家系的临床特点,并行spastin基因突变分析。方法　对整个家系进行详细的临床检查,先证者和另一例家系内患者进行了心肌酶学、头颅核磁共振成像(MRI)、胸髓MRI、肌电图、体感诱发电位检查。应用聚合酶链式反应 单链构象多态性(PCR SSCP)结合DNA序列分析方法,检测该家系中所有 5例患者和 4名有血缘关系的健康人及家系外 50名无血缘关系健康对照者spastin基因的突变情况。结果　先证者和家系内另一例SPG患者胸髓MRI显示胸髓萎缩;PCR SSCP检测发现家系内患者均出现异常SSCP电泳带,经测序证实为Leu378Gln突变。结论　该常染色体显性遗传SPG家系的患者具有典型的临床表现,为spastin基因Leu378Gln突变所致。     

遗传性痉挛性截瘫atlastin基因突变分析

目的 探讨中国人遗传性痉挛性截瘫（HSP）atlastin基因的突变特点,为HSP的基因诊断奠定基础。方法 应用聚合酶链反应一单链构象多态性（PCR-SSCP）结合DNA序列分析方法,对来自全国20例常染色体显性遗传HSP家系的先证者和10例散发性HSP患者进行了atlastin基因突变分析。结果 在20例常染色体显性遗传HSP家系的先证者和10例散发性HSP患者中均未发现异常SSCP条带,第7号外显子直接DNA序列分析亦无异常。结论 atlastin基因突变可能在中国人HSP患者中少见。     

遗传性痉挛性截瘫的临床和遗传特点

目的：探讨遗传性痉挛性截瘫的临床和遗传特点。方法：对39个家系113例患者的临床资料进行回顾性分析。结果：男：女为1：1.17，发病年龄2-58岁，平均21.4岁，30例以前发病占81.7％。有家族史者占89.4％，多呈常染色体显性遗传。近亲结婚家系占28.2％。单纯型24例，复杂型89例。双下肢肌力下降占65.5％，肌张力增高和腱反射亢进均为96.5％，病理征阳性68.1％。合并症中共济失调占46.9％，肌萎缩占32.7％，痴呆占18.6％。结论：本组遗传性痉挛性截瘫患者多于青少年或青年发病，女性多于男性，复杂型较单纯型多见，遗传方式以常染色体显性遗传多见，近亲结婚明显增加该病的发生。     

遗传性痉挛性截瘫一家系(SPG4)的临床与遗传学特点

目的 探讨遗传性痉挛性截瘫(HSP)4型患者的临床特点和基因突变. 方法观察HSP4型患者1个家系4例患者的临床特点,抽取家系5个成员的外周血,选择与已知HSP致病基因位点在物理距离上紧密连锁的微卫星分子STR进行标记.连锁分析并构建其单体型后进行突变筛选.结果 基因分型结果显示了D2S2351与D2S2255与致病基因不排除连锁.其他位点LOD值为负值排除连锁,因此初步定位于HSP致病基因(SPG)4,所对应的候选基因是spastin基因.突变筛查发现患者spastin基因第8外显子1168位置碱基A/G杂合突变.结论该HSP家系患者具有典型临床表现,为spastin基因第8外显子1168核苷酸的位置上A/G杂合突变所致.     

遗传性痉挛性截瘫

遗传性痉挛性截瘫是一种遗传性脊髓小脑变性疾病，主要表现为双下肢痉挛性截瘫。多为常染色体显性遣传，少数为常染色体隐性，极少Ｘ连锁隐性。目前已发现常显遗传ＨＳＰ基因位于１４ｑ１．２、２ｑ２１．２４和１５ｑ１１．１，常隐ＨＳＰ基因位于８号染色体，Ｘ隐ＨＳＰ位于Ｘｑ２８和Ｘｑ２１．３～２４。单纯型者仅表现为痉挛性截瘫，复杂型者可合并各种脊髓外损害。目前可采用安定、巴氯芬、妙纳等改善病人的肌痉挛。     

中国遗传性痉挛性截瘫的临床特点

目的 明确我国腓骨肌萎缩症的临床特点。方法 总结国内文献中报道的７８个家族，３５４例２及我院３９个家族、８１列患者的临床资料。结果 男：女约为１．７７：１，家族史阳性率６２．４％，其中常显、常隐、Ｘ隐性遗传分别为４１、１３、２个家系，同一家族患者发病年龄具有很高相关性。发病年龄１个月￣５５岁，平均１０．６岁，其中１￣２０岁起病占７１．２％；剪刀样步态７９．１％、双下肢肌张力增高８２．３％、肌力下降     

单纯型遗传性痉挛性截瘫临床特点分析

目的研究单纯型遗传性痉挛性截瘫的临床特点和诊断策略,提高认识。方法选择2006年10月-2013年2月门诊或住院诊断与治疗的单纯型遗传性痉挛性截瘫患者,分析其临床特点,并对患者进行痉挛性截瘫量表评价。结果共纳入33例患者,男性21例、女性12例,其中13例(39.39%)有阳性家族史,11例(11/13)为常染色体显性遗传。平均发病年龄(20.35±15.55)岁,平均病程(12.77±9.83)年。病程中均出现锥体束损害体征,表现为双侧下肢肌张力增高、腱反射亢进、病理征阳性,部分累及上肢。29例呈典型剪刀步态,5例合并弓形足,5例出现胸髓萎缩,2例肌电图检查提示合并周围神经损害。基因突变筛查发现,SPG4基因第10～17外显子区域大片段缺失突变(4/11)。男性及女性患者年龄、平均发病年龄、平均病程、痉挛性截瘫量表评分差异无统计学意义(均P>0.05),有家族史和无家族史患者平均发病年龄、平均病程、痉挛性截瘫量表评分差异亦无统计学意义(均P>0.05)。结论单纯型遗传性痉挛性截瘫发病年龄差异较大,男性多于女性,多为常染色体显性遗传。临床表现以下肢锥体束损害为主,可合并膀胱功能损害、周围神经损害症状,性别和家族史不影响该病临床特征。结合临床表现、阳性家族史、脊柱MRI检查等可协助诊断,明确诊断需进行相关基因学检测。     

Autosomal dominant hereditary spastic paraplegia: report of a large italian family with R581X spastin mutation

We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia (ADHSP). On the basis of maximum LOD score of 1.94 at theta (max)=0 with marker D2S367, we obtained suggestive evidence for linkage of ADHSP to SPG4 locus. Denaturing high-performance liquid chromatography (DHPLC) and direct sequence analysis allowed us to identify a nonsense mutation (1741* C>T) in exon 17 of the Spastin gene. This transition, carried by all the affected family members and two apparently healthy individuals, lead to truncation of the last 36 amino acids in the C-terminus of the protein. These results confirm the existence of mutation in the SPG4 gene with a reduced penetrance, indicating that other genetic or environmental factors are required to trigger full-blown disease.

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Sommario Le paraparesi spastiche ereditarie (HSP) rappresentano un gruppo clinicamente e geneticamente eterogeneo di malattie neurodegenerative, caratterizzate da progressiva spasticità ed iperreflessia crurale. La maggior parte delle HSP (70%–80%) presenta una trasmissione di tipo autosomico dominante ed è principalmente determinata da mutazioni nel gene della Spastina (SPG4) che codifica una proteina appartenente alla famiglia delle AAA (Adenosine triphosphatases Associated with diverse cellular Activities). In questo studio descriviamo una famiglia con una forma autosomica dominante di paraparesi spastica ereditaria, clinicamente non complicata. Mediante analisi di linkage è stata individuata un associazione con il locus SPG4. La DHPLC e il sequenziamento diretto hanno permesso l’individuazione di una mutazione nonsense (1741* C>T) nell’esone17 del gene della Spastina. Questa transizione, presente in tutti gli individui affetti della famiglia e in due soggetti clinicamente sani, porta alla formazione di una proteina priva degli ultimi 36 aminoacidi dell’estremità C-terminale. Questi risultati confermano l’esistenza di mutazioni del gene SPG4 con penetranza incompleta che in aggiunta ad altri fattori, genetici e non genetici, possono portare alla genesi del fenotipo clinico.

     

Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression, both within and among families. The most-common cause of autosomal dominant HSP is mutation of the gene encoding spastin, a protein of uncertain function. We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype. One (S44L) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue (P45Q). In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin, L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations. Using a bioinformatics approach, we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline-directed serine/threonine cyclin-dependent kinases (Cdks). Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay, suggesting that this serine residue may be phosphorylated by a different Cdk. Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most-common form of HSP.     

A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a Chinese family

A total of eight loci for autosomal dominant hereditary spastic paraplegia (ADHSP) has been mapped to chromosome 14q, 2p, 15q, 8q, 10q, 12q, 19q, 2q, respectively, among which the SPG4 gene on chromosome 2p21–22 encoding spastin, an ATPase of the AAA family, accounts for 40–50% of all ADHSP families and is expressed in both adult and fetal tissues. In this work, we reveal a novel insertion mutation in exon 11 of the SPG4 gene found in a big Chinese family composed of 47 members, including 20 affected ones, using linkage analysis. The mutation was well demonstrated to be the cause of loss of production of the functional protein by pre-termination of translation in AAA cassette region. To our knowledge, this is the first report of spastin mutation in China.     

Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia

BACKGROUND: Hereditary spastic paraplegia is a group of genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs. The most common form of hereditary spastic paraplegia is caused by mutations in the spastin gene (SPG4), which encodes spastin, an adenosine triphosphatase associated with various cellular activities protein. OBJECTIVE: To investigate the Chinese patients with hereditary spastic paraplegia for mutations in SPG4. METHODS: DNA samples from 31 unrelated patients were analyzed for mutations in SPG4 by single-strand conformation polymorphism analysis and direct sequencing. All DNA samples were screened for mutations by the polymerase chain reaction, followed by electrophoresis and silver staining. Each new variant identified was analyzed in 50 control subjects to determine whether it is a polymorphism or a mutation. RESULTS: Three novel mutations were detected in 4 affected individuals, including 2 missense mutations (T1258A and A1293G) and 1 deletion mutation (1668-1670delCTA). CONCLUSIONS: To our knowledge, this is the first report of SPG4 mutations in the People's Republic of China. The percentage of involved Chinese families with autosomal dominant hereditary spastic paraplegia with an SPG4 mutation is 18% (4/22), lower than the estimated 40% linked to this locus.     

遗传性痉挛性截瘫患者MJD1基因的突变分析

目的探讨中国汉族人群中遗传性痉挛性截瘫(Hereditary Spastic Paraplegia,HSP或SPG)患者的MJD1基因突变特点,进一步探索HSP和遗传性脊髓小脑性共济失调(Spinocerebellar Ataxia,SCA)的遗传和临床异质性。方法应用聚合酶链反应、8%变性聚丙烯酰胺凝胶电泳和DNA T载体连接测序等方法对78例临床诊断为HSP的患者进行MJD1基因突变分析。结果在18个HSP家系中检出SCA3/MJD1家系2个,占11.1%,该2例家系均为常染色体显性遗传,2例家系先证者在临床上符合HSP的诊断标准,突变的MJD1等位基因CAG三核苷酸异常重复次数分别为65和69次,散发的HSP病例未发现MJD1等位基因的异常。结论HSP和SCA都具有明显的临床和遗传异质性,其表型在临床上有相互交叉现象,部分SCA3/MJD1患者临床上可为典型的痉挛性截瘫特征而无任何明显的共济失调表现。对临床表现为HSP的患者,尤其是有明显阳性家族史的患者进行MJD1基因诊断可以弥补HSP临床诊断的不足。