Beetz C, Nygren A O H, Schickel J, Auer-Grumbach M, Bürk K, Heide G, Kassubek J, Klimpe S, Klopstock T, Kreuz F, Otto S, Schüle R, Schöls L, Sperfeld A-D, Witte O W, Deufel T
Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, D-07740 Jena, Germany.
Neurology. 2006 Dec 12;67(11):1926-30. doi: 10.1212/01.wnl.0000244413.49258.f5. Epub 2006 Oct 11.
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.
To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP.
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.
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.
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.
遗传性痉挛性截瘫（HSP）是一种具有遗传异质性的神经退行性疾病。常染色体显性遗传性痉挛性截瘫最常见的病因是痉挛蛋白（SPG4位点）突变，但尽管与SPG4连锁，仍有部分家系经传统筛查未发现突变。
确定常染色体显性遗传性痉挛性截瘫中痉挛蛋白基因组拷贝数变异的频率。
我们开发并验证了一种针对痉挛蛋白和SPG3A（另一个常与常染色体显性遗传性痉挛性截瘫相关的基因）的多重连接依赖探针扩增检测方法。在一项多中心研究中，我们随后对65例常染色体显性遗传性痉挛性截瘫的先证者进行了研究，这些患者先前痉挛蛋白突变筛查均为阴性。对独立的二次样本、其他家庭成员及cDNA进行分析以确认阳性结果。
在12例患者（18%）中发现异常的多重连接依赖探针扩增图谱。这些异常仅影响痉挛蛋白，表现为缺失，与疾病共分离，且在很大程度上具有家系特异性。痉挛蛋白内部缺失导致相应缩短的转录本表达，其稳定性各异。痉挛蛋白缺失携带者的发病年龄与其他痉挛蛋白突变携带者无异。
痉挛蛋白部分缺失而非痉挛蛋白扩增及SPG3A拷贝数变异是常染色体显性遗传性痉挛性截瘫的一个被低估的病因。痉挛蛋白部分缺失可能通过单倍剂量不足发挥作用。
