Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases
Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases
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DOI：
10.1136/jmg.2005.035311
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发表时间：
2006-03-01
影响因子：
4
通讯作者：
Durr, A
中科院分区：
文献类型：
--
作者：
Depienne, C;Tallaksen, C;Durr, A
背景：SPG 4编码AAA蛋白家族成员spastin，是常染色体显性遗传性痉挛性截瘫的主要致病基因。它占10-40%的家庭与纯粹的（或最终复杂的）遗传性痉挛性截瘫（HSP.Objective：评估SPG 4突变的频率在痉挛性截瘫患者，但没有家族史.Methods：146例主要是欧洲先证者进行性痉挛性截瘫（103例与纯粹的痉挛性截瘫和43个附加功能）进行了研究。排除了截瘫的主要神经学原因。没有人有截瘫的家族史。通过DHPLC筛选SPG 4基因的17个编码外显子中的突变的DNA。通过直接测序表征序列变体。一组600条对照染色体被用来排除polymorphis.Results：突变的总体率为12%; 19个不同的突变被确定在18例，其中13个是新的。在一个家庭中，父母双方都被检查并发现是正常的，突变是由无症状的母亲传播的，这表明降低了遗传率。其他患者的父母无法进行分析，但报告为正常。没有证据表明存在新生突变。在这些明显孤立的患者中发现的突变大多是错义型，往往与一个不太严重的表型比以前描述的患者与遗传mutations.Conclusions：SPG 4基因突变的意外存在，在散发性痉挛性截瘫患者表明，基因检测应在个人与纯或复杂的痉挛性截瘫没有家族史。
Background: SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10-40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP).Objective: To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories.Methods: 146 mostly European probands with progressive spastic paraplegia were studied ( 103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms.Results: The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations.Conclusions : The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.