High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia
High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia
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DOI：
10.1212/01.wnl.0000244413.49258.f5
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发表时间：
2006-12-12
期刊：
影响因子：
9.9
通讯作者：
Deufel, T.
中科院分区：
文献类型：
--
作者：
Beetz, C.;Nygren, A. O. H.;Deufel, T.
背景：遗传性痉挛性截瘫（HSP）是一种遗传异质性神经退行性疾病。常染色体显性 HSP 的最常见原因是 SPAST（SPG4 位点）突变，但其他家系尽管与 SPG4 存在连锁，但通过常规筛查仍呈阴性突变。目的：确定常染色体显性 HSP 中 SPAST 基因组拷贝数畸变的频率。方法：我们开发并验证了一种针对 SPAST 和 SPG3A 的多重连接依赖性探针扩增测定法，SPAST 和 SPG3A 是常染色体显性 HSP 中经常涉及的另一个基因。在一项多中心研究中，我们随后调查了 65 名患有常染色体显性 HSP 的指标患者，所有这些患者之前均被筛查为 SPAST 突变阴性。对独立的二级样本、其他家庭成员和 cDNA 进行了分析，以确认阳性结果。结果：在 12 例 (18%) 病例中发现了异常 MLPA 特征。它们专门影响 SPAST，代表缺失，与疾病分离，并且很大程度上具有谱系特异性。内部 SPAST 缺失需要表达相应缩短的转录本，其稳定性各不相同。 SPAST 缺失携带者的发病年龄与其他 SPAST 突变相关的年龄没有差异。结论：部分 SPAST 缺失，而非 SPAST 扩增和 SPG3A 拷贝数畸变，代表了常染色体显性遗传性痉挛性截瘫的被低估的原因。部分 SPAST 缺失可能通过单倍体不足起作用。
Background: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4. Objective: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. Methods: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. Results: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. Conclusions: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.