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Hereditary spastic paraplegia: clinical genetic study of 15 families

机译:遗传性痉挛性截瘫:15个家庭的临床遗传学研究

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摘要

Background: Autosomal dominant hereditary spastic paraplegia (ADHSP) is mainly caused by mutations in \udthe SPG4 gene, which encodes a new member of the AAA (adenosine triphosphatases associated with \uddiverse cellular activities) protein family (spastin). Accumulation of genotype-phenotype correlation is \udimportant for better understanding of SPG4-linked hereditary spastic paraplegia.\udObjectives: To perform a clinical and genetic study of families with ADHSP and to perform the functional\udanalysis of the founder mutation discovered in the SPG4 gene.\udDesign: Genetic and clinical study.\udPatients: Fifteen unrelated families with ADHSP originating from southern Scotland.\udMain Outcome Measures: Clinical assessment, linkage analysis, haplotype study, expression of mutant \udspastin protein in cultured cells.\udResults: Nine families with ADHSP were linked to the SPG4 locus at 2p21-p24. Sequence analysis of SPG4\udshowed a novel N386S mutation in all 9 of these families. Expression of mutant spastin showed aberrant\uddistribution in cultured cells. Haplotype analysis suggested the existence of a common founder. Clinical \udexamination of the affected members carrying the mutation showed phenotypic variations including \udbroad range of age at onset and disease duration and additional neurologic features such as mental \udretardation. Magnetic resonance imaging demonstrated unique features, including thin corpus callosum \udand atrophy of the cerebellum in 2 patients. Linkage and sequence analyses showed no evidence of linkage \udto the currently known ADHSP loci in the remaining 6 families.\udConclusions: A founder SPG4 mutation N386S was identified in the families with ADHSP originating from \udsouthern Scotland. Clinical investigation showed intrafamilial and interfamilial phenotypic variations. The \udgenetic study demonstrated evidence of further genetic heterogeneity in ADHSP.
机译:背景:常染色体显性遗传性痉挛性截瘫(ADHSP)主要是由SPG4基因突变引起的,该基因编码AAA(与细胞多样性活动相关的三磷酸腺苷)蛋白家族(spastin)的新成员。基因型-表型相关性的积累对于更好地了解与SPG4相关的遗传性痉挛性截瘫至关重要。\ ud目的:对ADHSP家族进行临床和遗传研究,并对在SPG4基因中发现的创始人突变进行功能性\ udana分析\ ud设计:遗传和临床研究。\ ud患者:来自苏格兰南部的十五个ADHSP无关家族。\ ud主要结果指标:临床评估,连锁分析,单倍型研究,突变型\ udspastin蛋白在培养细胞中的表达。\ ud结果:九ADHSP家族与SPG4基因座位于2p21-p24。 SPG4 \ ud的序列分析显示,在这9个家族中都有一个新的N386S突变。突变spastin在培养细胞中表达异常\ ud分布。单倍型分析表明存在一个共同的创始人。携带突变的受影响成员的临床脱甲氨showed呤显示表型变异,包括发作时的广泛年龄范围和疾病持续时间,以及其他神经系统特征,例如精神智力低下。磁共振成像显示出独特的特征,包括2例患者的薄thin体和小脑萎缩。连锁和序列分析显示,在剩余的6个家族中没有与目前已知的ADHSP基因座连锁的证据。\ ud结论:在源自苏格兰南部的ADHSP家族中发现了创始人SPG4突变N386S。临床研究显示家族内和家族间表型变异。预算研究证明了ADHSP中进一步遗传异质性的证据。

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