一个遗传性脊髓小脑共济失调大家系的连锁分析

目的检测一遗传性脊髓小脑共济失调家系的遗传缺陷基础。方法收集湖南地区一遗传性脊髓小脑共济失调家系，对患者的临床表型进行评估。采集家系成员48人（包括患者8人）外周静脉血提取基因组DNA，对候选染色体区域选取合适的微卫星标记，采用多重PCR和电泳方法进行基因组扫描，数据经Linkage软件包进行连锁分析以对该家系进行基因定位，以确定疾病相关基因所在的染色体区域。结果两点间连锁分析结果显示，该家系在脊髓小脑共济失调遗带瘟童SCAl、SCA27SCA3、SCA57SCA67SCA77SCA87SCAl07SCAl，？SCAl27SCAl37SCAl47SCAl57SCAl67SCAl7、SCA20、SCA27、SCA28、SCA31、DRPLA处的最大LOD值仅为0．49，提示该家系致病基因与这些位点无连锁关系。结论排除该家系与目前已知的20个常染色体显性小脑共济失调相关染色体位点的连锁关系，提示可能存在其它未知的SCAs位点。     

橄榄桥脑小脑萎缩一家系的临床和遗传学研究

目的 对一个常染色体显性遗传橄榄桥脑小脑萎缩(olivopontocerebellar atrophy,OPCA)家系进行临床诊断,探讨其临床特点并明确其基因诊断.方法 完成家系调查,对包括先证者在内的家系成员进行神经科体检,行头部核磁共振(magnetic resonance imaging,MRI)等辅助检查,并进行基因诊断.结果 该家系呈常染色体显性遗传,其中两例成员有明显异常临床表现,家族史调查显示另有9例有相似临床表现的成员已去世,头部MRI示小脑、脑干以及桥脑萎缩明显.结合家族史、临床表现以及MRI检查结果,其诊断符合橄榄桥脑小脑萎缩.对所有家系成员进行致病基因分析发现,脊髓小脑共济失调2型(spinocerebellar ataxia type 2,SCA2)、3型(SCA3)、7型(SCA7)、12型(SCA12)以及齿状核红核苍白球丘脑下部核萎缩(dentatorubral-pallidoluy-sian atrophy,DRPLA)致病基因检测均正常.10例健康对照SCA1目的片段CAG重复数为29～37,而2例患者异常等位基因CAG重复数分别为53和67,5例无症状家系成员中,1例CAG重复数为57,确诊为症状前患者,另外4例CAG重复数在29～37之间,排除患病可能.结论 该家系为CAG动态突变引起的橄榄桥脑小脑萎缩,临床特征存在异质性,基因诊断符合SCA1.     

马查多-约瑟夫病的分子遗传学研究进展

迄今为止,至少已定位了常染色体显性遗传小脑件共济失调28种不同的基因型,已克隆18个致病基因,其中对不同种族和地域的研究表明,马查多-约瑟夫病(Machado-Joseph disease,MJD),即脊髓小脑性共济失调3型(spinoocerebellar ataxia type 3,SCA3),是世界上最常见的SCAs亚型.它是由位于致病基因MJD13'端的CAG三核苷酸重复扩增突变引起的一种具有明显的临床和遗传异质性的神经系统退行性疾病.作者就SCA3/MJD的分子遗传学方面的研究进展进行综述.     

浙江沿海一家系脊髓小脑性共济失调的基因突变检测与临床表现

目的 探讨浙江沿海脊髓小脑性共济失调的基因突变检测与临床表现.方法 对该家系18例患者的临床表现、头颅MRI等辅助检查资料分析,并与10名家系中未发病成员及12名非血缘的健康人进行SCA31MJD基因CAG三核苷酸重复数目比较.结果 家系18例患者均为SCA3/MJD型,同时检测出家系中未发病对照组有2例为SCA31MJD型基因携带者.产物测序结果家系对照组与健康对照组CAG重复数为14～27次;SCA患者CAG重复数为67～82次;SCA3/MJD携带者CAG重复数为28～45次.在现存三代18例患者中,每代均有患者,男女均受累,起病年龄平均38岁,以行走不稳、动作笨拙和言语含糊为突出表现,MRI检测结果小脑、脑干明显萎缩.结论 在我国沿海存在SCA3/MJD家系遗传.临床均以共济失调和构音障碍为突出,CAG重复数目检测可为基因诊断和症状前诊断提供依据.     

齿状核红核苍白球路易氏体萎缩症家系的临床和基因突变分析

目的 探讨齿状核红核苍白球路易氏体萎缩症(dentatorubral-pallidoluysian atrophy,DRPLA)患者的临床特征和基因突变特点.方法 应用基于荧光标记的毛细管电泳片段分析法对708个常染色体显性遗传脊髓小脑共济失调(spinocerebellar ataxias,SCA)家系的先证者和119例临床拟诊为SCA的散发患者进行DRPLA基因CAG重复次数分析.结果 共检出3例患者存在DRPLA基因CAG重复扩展突变.片段分析显示其CAG重复次数分别为16/58、16/58和14/54次,长片段重复次数达到异常范围.3个家系的先证者均为成年起病,以共济失调为主要症状,患者可伴发抽搐、颈部扭转等表现.结论 在827例共济失调病例中仅发现3例DRPLA,说明该病在中国人群中较为罕见.DRPLA的临床表现复杂多样,存在变异.对DRPLA患者的临床特征和突变特点的细致分析有助于同其他SCA类型进行鉴别诊断.     

中国大陆遗传性脊髓小脑型共济失调患者PURATROPHIN-1基因c.-16C＞T突变研究

目的 研究中国大陆遗传性脊髓小脑型共济失调(spinocerebellar ataxia,scA)患者PURATROPHIN-1 c.-16C＞T突变分布.方法 应用聚合酶链反应.限制性片段长度多态技术,对已经排除了SCA1、SCA2、SCA3、SCA6、SCA7、SCA17和齿状核.红核.苍白球路易体萎缩的68个常染色体显性遗传SCA家系的先证者及119例散发SCA患者进行PURATROPHIN-1基因c.-16C＞T突变检测.结果 未发现PUPURATROPHIN-1基因c.-16C＞T突变.结论 PURATROPHIN-1基因c.-16C＞T突变在中国大陆SCA人群中罕见.     

黑龙江省遗传性脊髓小脑共济失调两家系报告

遗传性脊髓小脑共济失调(Spinocerebellar Ataxias,SCA)是遗传性共济失调的主要类型,包括SCA10～SCA29,根据基因、染色体位点及生化产物分类,SCA中大多数是SCA1/2/3/6/6、和8亚型,其余类型很少见[1]。遗传方式主要为常染色体显形遗传。遗传早现现象是SCA的典型表现,另外SCA还与人种有关,中国患者     

一个遗传性共济失调7型家系的基因突变分析

目的 研究1个遗传性共济失调7型回族家系的临床表现与基因突变特点.方法 应用聚合酶链反应、分子克隆及测序等方法对1个临床诊断为遗传性共济失调的回族家系进行SCA7基因检测,对异常片段进行分子克隆测序.结果 证实该家系为遗传性共济失调7型家系,视网膜退行性变为其相对独特的临床表现.先证者父亲异常片段CAG重复为46次;先证者异常片段CAG重复次数为54次,发病年龄较父代提前22年.结论 报告1个遗传性共济失调7型回族家系,该亚型明显的遗传早现及病程进展与CAG重复次数的不稳定扩增相关.     

一个遗传性共济失调3型家系中致病ATXN3中间类型等位基因分析

目的 研究遗传性共济失调3型中间类型等位基因致病表型的临床表现与基因突变特点.方法 应用PCR、毛细微管电泳、分子克隆及测序等方法 对1个临床诊断为遗传性共济失调家系进行ATXN3基因检测,对异常片段进行分子克隆测序.结果 证实该家系为遗传性共济失调3型家系,先证者异常片段CAG重复次数为43次;患者两个儿子异常片段重复分别为41、64次.结论 中间类型等位基因在两代间遗传是不稳定的,重复次数的改变是双向的,43次CAG重复是目前报道的遗传性共济失调3型发病患者最小不稳定重复次数.本家系的研究结果 进一步缩短了正常CAG重复次数与异常重复次数之间的差距.     

一个遗传性共济失调3型家系中致病ATXN3中间类型等位基因分析

目的 研究遗传性共济失调3型中间类型等位基因致病表型的临床表现与基因突变特点.方法 应用PCR、毛细微管电泳、分子克隆及测序等方法 对1个临床诊断为遗传性共济失调家系进行ATXN3基因检测,对异常片段进行分子克隆测序.结果 证实该家系为遗传性共济失调3型家系,先证者异常片段CAG重复次数为43次;患者两个儿子异常片段重复分别为41、64次.结论 中间类型等位基因在两代间遗传是不稳定的,重复次数的改变是双向的,43次CAG重复是目前报道的遗传性共济失调3型发病患者最小不稳定重复次数.本家系的研究结果 进一步缩短了正常CAG重复次数与异常重复次数之间的差距.     

遗传性脊髓小脑型共济失调的CAG三核苷酸突变检测

目的 评价ＳＣＡ１、ＳＣＡ２、ＳＣＡ３／ＭｊＤ、ＳＣＡ６、ＳＣＡ７和ＤＲＰＬＡ的ＣＡＧ三核苷酸异常扩增突变「（ＣＡＧ）ｎ」,在中国人遗传性脊髓小脑型共济失调（ｓｐｉｎｏｃｅｒｅｂｅｌｌａｒ ａｔａｘｉａ,ＳＣＡ）患者的分布频率。方法 经聚合酶链反应、变性聚丙烯酰按凝胶电泳和银染显带技术,检测分析了８５个中国人常染色体显性遗传ＳＣＡ家系（其中患者１６７例）和３７例散发ＳＣＡ患者的ＳＣＡ１、ＳＣＡ２、     

Genetics of the SCA6 gene in a large family segregating an autosomal dominant "pure" cerebellar ataxia

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar degeneration caused by the expansion of a CAG trinucleotide repeat in the CACNA1A gene. Mutations in patients are characterised by expanded alleles of between 21 and 30 repeat units and by extreme gonadal stability when transmitted from parents to children. We have investigated the SCA6 mutation in a large Spanish kindred in which previously reported spinocerebellar SCA genes and loci had been excluded. We observed a 23 CAG repeat expanded allele in the 13 clinically affected subjects and in three out of 10 presymptomatic at risk subjects. Transmission of the mutant allele was stable in six parent to child pairs and in 29 meioses through the pedigree. Linkage analysis with the SCA6-CAG polymorphism and marker D19S221 confirmed the location of SCA6 on chromosome 19p13. The molecular findings in this large family confirm the expansion of the CAG repeat in the CACNA1A gene as the cause of SCA6 and the high meiotic stability of the repeat.     

脊髓小脑性共济失调12型维吾尔族一家系的基因突变及临床特点

目的 研究新疆地区维吾尔族脊髓小脑性共济失调12亚型(spinocerebellar ataxia type 12,SCA12)致病基因的CAG三核苷酸病理重复次数范围及临床特点.方法 依据Harding标准,收集一个维吾尔族家系,应用聚合酶链反应、琼脂糖凝胶电泳、T载体分子克隆技术并结合酶切鉴定、直接测序等技术对其中6例患者、54例家系"健康"个体进行分子遗传学诊断,基因诊断为SCA12型,同时对致病基因CAG三核苷酸病理重复次数进行突变分析.结果 发现该家系SCA12型患者6例,症状前患者13例.5例经基因重组检测发现:患者异常等位基因CAG重复数目分别是47次、51次、52次、53次;症状前患者是48次;其中在连续CAG重复中间有单个碱基C、A、G的互相替换.结论 SCA12型的47次CAG病理重复次数为国内外报道的最小CAG病理重复次数;国内首次对维吾尔族SCA12型的基因突变特点进行分析,从而对于该类疾病的准确分类、病因探讨、治疗、产前诊断等具有重要的意义.

Abstract：

Objective To investigate the CAG trinucleotide repeat expansion and clinical characteristics of a Chinese Uygur family with spinocerebellar ataxia type 12 (SCA12) in Xinjiang Uygur Autonomous Region. Methods In the Uygur SCA12 family, 6 patients and 54 "healthy" members were analyzed by polymerase chain reaction, agarose gel electrophoresis, recombinant DNA technology by T-Vector cloning and restriction enzyme digestion, and direct sequencing. The diagnosis of SCA12 was confirmed. The CAG trinucleotide expansion was also analyzed. Results Six members in the family were diagnosed as SCA12 patients and 13 were presymptomatic. Five of them were successfully detected by sequencing. The CAGrepeat numbers of 4 patients were 47, 51, 52 and 53, respectively, and 48 in the presymptomatic patient.We also observed that in the CAG repeat region there was replacement of single nucleotide C, A or G.Conclusion Forty-seven CAG repeats of SCA12 has been reported as the shortest known causative expanded alleles. The present study is the first report of the characteristics of SCA12 gene mutation in Chinese. It will provide basis for the accurate classification, disease etiology, treatment and prenatal diagnosis of this disease.     

脊髓小脑性共济失调12型维吾尔族一家系的基因突变及临床特点

目的 研究新疆地区维吾尔族脊髓小脑性共济失调12亚型(spinocerebellar ataxia type 12,SCA12)致病基因的CAG三核苷酸病理重复次数范围及临床特点.方法 依据Harding标准,收集一个维吾尔族家系,应用聚合酶链反应、琼脂糖凝胶电泳、T载体分子克隆技术并结合酶切鉴定、直接测序等技术对其中6例患者、54例家系"健康"个体进行分子遗传学诊断,基因诊断为SCA12型,同时对致病基因CAG三核苷酸病理重复次数进行突变分析.结果 发现该家系SCA12型患者6例,症状前患者13例.5例经基因重组检测发现:患者异常等位基因CAG重复数目分别是47次、51次、52次、53次;症状前患者是48次;其中在连续CAG重复中间有单个碱基C、A、G的互相替换.结论 SCA12型的47次CAG病理重复次数为国内外报道的最小CAG病理重复次数;国内首次对维吾尔族SCA12型的基因突变特点进行分析,从而对于该类疾病的准确分类、病因探讨、治疗、产前诊断等具有重要的意义.     

脊髓小脑性共济失调12型维吾尔族一家系的基因突变及临床特点

目的 研究新疆地区维吾尔族脊髓小脑性共济失调12亚型(spinocerebellar ataxia type 12,SCA12)致病基因的CAG三核苷酸病理重复次数范围及临床特点.方法 依据Harding标准,收集一个维吾尔族家系,应用聚合酶链反应、琼脂糖凝胶电泳、T载体分子克隆技术并结合酶切鉴定、直接测序等技术对其中6例患者、54例家系"健康"个体进行分子遗传学诊断,基因诊断为SCA12型,同时对致病基因CAG三核苷酸病理重复次数进行突变分析.结果 发现该家系SCA12型患者6例,症状前患者13例.5例经基因重组检测发现:患者异常等位基因CAG重复数目分别是47次、51次、52次、53次;症状前患者是48次;其中在连续CAG重复中间有单个碱基C、A、G的互相替换.结论 SCA12型的47次CAG病理重复次数为国内外报道的最小CAG病理重复次数;国内首次对维吾尔族SCA12型的基因突变特点进行分析,从而对于该类疾病的准确分类、病因探讨、治疗、产前诊断等具有重要的意义.     

Trinucleotide expansions in the SCA7 gene in a large family with spinocerebellar ataxia and craniocervical dystonia

Spinocerebellar ataxia type 7 is a rare autosomal dominant cerebellar ataxia (ADCA). Herein, we describe the molecular and clinical findings in patients within six generations of a large Chinese family with spinocerebellar ataxia. To identify the genetic cause(s), 4 affected patients and 26 asymptomatic relatives were recruited for the study. Molecular screening of the SCA1 and SCA7 genes was carried out by subcloning and direct PCR-sequencing methods. Both neurological and ophthalmic examinations were performed to investigate the clinical characteristics of the disease. The patients had typical cerebellar ataxia, achromatopsia and macular degeneration, and displayed a rare phenotype manifesting as a combination of cerebellar ataxia and craniocervical dystonia. Mutational analysis of the SCA7 genes demonstrated expanded CAG-repeats in the four patients. In conclusion, we identified expanded CAG-repeats in the SCA7 gene within members of a large Chinese family with spinocerebellar ataxia. The defined phenotypic characteristics of the patients may be helpful for clinical diagnosis and genetic typing of new patients.     

Analysis of SCA1, DRPLA,MJD, SCA2, and SCA6 CAG repeats in 48 portuguese ataxia families

The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:134–138, 1998. © 1998 Wiley-Liss, Inc.     

Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission

The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed, translated CAG tract that is expanded in SCA7 patients. We have determined expansions in 73 individuals from 17 SCA7 kindreds and compared them with repeat lengths of 180 unaffected individuals. Subjects with abnormal expansions comprise 59 clinically affected individuals and 14 at-risk currently unaffected individuals predicted to carry the mutation by haplotype analysis. For expanded alleles, CAG repeat length correlates with disease progression and severity and correlates inversely with age of onset. Increased repeat lengths are seen in generational transmission of the disease allele, consistent with the pattern of clinical anticipation seen in these kindreds. Repeat lengths in expanded alleles show somatic mosaicism in leukocyte DNA, suggesting that these alleles are unstable within individuals as well as between generations. Although dynamic repeat expansions from paternal transmissions are greater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of the repeat expansion.      

脊髓小脑共济失调患者CAG病理重复次数检测

目的 研究中国汉族人群脊髓小脑性共济失调(spinocerebellar ataxia,SCA)1、2、3、6、7、12、17亚型致病基因的CAG三核苷酸病理重复次数范围.方法 应用聚合酶链反应、琼脂糖凝胶电泳、T载体克隆重组DNA技术并结合直接测序等技术对559例临床诊断为SCA的患者(363例常染色体显性遗传先证者,196例散发患者)进行SCA1、SCA2、SCA3/马查多-约瑟夫病(Machado-Joseph disease,MJD)、SCA6、SCA7、SCA12和SCA17致病基因CAG三核苷酸病理重复次数突变分析.结果 在559例SCA患者中,共检测出SCA1患者23例,CAG病理重复次数范围39～60次,平均(51.09±4.88)次;SCA2患者32例,CAG病理重复次数范围36～51次,平均(40.34±4.40)次;SCA3/MJD患者305例,CAG病理重复次数范围49～86次,平均(73.84±5.07)次;SCA6患者9例,CAG病理重复次数范围23～29次,平均(25.56±1.94)次;SCA7患者27例,CAG病理重复次数范围38～71次,平均(58.22±10.90)次;SCA12患者3例,CAG病理重复次数范围51～52次,平均(51.33±0.58)次;SCA17患者2例,CAG病理重复次数范围53～55次,平均(54.00±1.41)次.结论 SCA1的39次CAG病理重复、SCA3/MJD的49次CAG病理重复和SCA12的51次CAG病理重复为国内或国外报道的最小CAG病理重复次数;SCA3/MJD的86次CAG病理重复为国内外报道的最大CAG病理重复次数;SCA17为国内首次发现的SCA亚型;首次建立中国汉族人群不同SCA亚型CAG三核苷酸病理重复次数范围标准.