Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements.
Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements.
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DOI：
10.1186/1471-2377-10-17
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发表时间：
2010-03-09
期刊：
影响因子：
2.6
通讯作者：
Haldre S
中科院分区：
文献类型：
--
作者：
Braschinsky M;Tamm R;Beetz C;Sachez-Ferrero E;Raukas E;Lüüs SM;Gross-Paju K;Boillot C;Canzian F;Metspalu A;Haldre S
遗传性痉挛性截瘫（HSP）是一种临床和遗传异质性疾病，可以是常染色体显性，常染色体隐性或X连锁疾病。该疾病最常见的常染色体显性形式来自SPAST基因的突变。本研究的目的是分析49例诊断为HSP从爱沙尼亚人口的序列变异的SPAST基因，并描述相关的表型。健康对照组（n = 100）没有HSP家族史也进行了分析。使用变性高效液相色谱法（DHPLC）和多重连接依赖性探针扩增（MLPA）试验筛选所有患者样本。对具有异常DHPLC和MLPA谱的样品进行测序，在对照样品中测序相同的区域。49例HSP患者中有19例（38.8%）发现SPAST序列变异，其中12例为致病性突变。在后一组中有一例散发病例。8例患者有纯HSP和4种复合HSP。12个变异体被鉴定：7个致病性（c.1174-1G>C、c.1185delA、c.1276C>T、c.1352_1356delGAGAA、c.1378C>A、c.1518_1519insTC、c.1841_1842insA）和5个非致病性（c.131C>T、c.484G>A、c.685A>G、c.1245+ 202 delG、c.1245+ 215 G>C）。这些突变中只有2个以前被描述过（c.131C>T，c.1245+ 202 delG）。c.1174-1G>C、c.1276 C>T、c.1378 C>A三个突变存在家族内分离。本研究鉴定了SPAST基因的新变体，包括良性错义变体和短插入/缺失。未发现大的重排。基于这些数据，7个新的HSP致病变异体与临床表型相关。
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder that can be an autosomal-dominant, autosomal-recessive, or X-linked disease. The most common autosomal-dominant form of the disease derives from mutations in the SPAST gene. The aim of this study was to analyze 49 patients diagnosed with HSP from the Estonian population for sequence variants of the SPAST gene and to describe the associated phenotypes. Healthy control individuals (n = 100) with no family history of HSP were also analyzed. All patient samples were screened using denaturing high performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) assay. Samples with abnormal DHPLC and MLPA profiles were sequenced, with the same regions sequenced in control samples. Sequence variants of SPAST were identified in 19/49 HSP patients (38.8%), twelve among them had pathogenic mutations. Within the latter group there was one sporadic case. Eight patients had pure, and four - complex HSP. The twelve variants were identified: seven pathogenic (c.1174-1G>C, c.1185delA, c.1276C>T, c.1352_1356delGAGAA, c.1378C>A, c.1518_1519insTC, c.1841_1842insA) and five non-pathogenic (c.131C>T, c.484G>A, c.685A>G, c.1245+202delG, c.1245+215G>C). Only 2 of these mutations had previously been described (c.131C>T, c.1245+202delG). Three mutations, c.1174-1G>C, c.1276 C>T, c.1378C>A, showed intrafamilial segregation. This study identified new variants of the SPAST gene which included benign missense variants and short insertions/deletions. No large rearrangements were found. Based on these data, 7 new pathogenic variants of HSP are associated with clinical phenotypes.
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