Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.
Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China.
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中国遗传性痉挛性截瘫的临床谱和遗传图谱
DOI：
10.1186/s13024-018-0269-1
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发表时间：
2018-07-06
影响因子：
15.1
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Dong EL;Wang C;Wu S;Lu YQ;Lin XH;Su HZ;Zhao M;He J;Ma LX;Wang N;Chen WJ;Lin X
背景：遗传性痉挛性截瘫（HSP）是一类影响皮质脊髓束的罕见神经退行性疾病。迄今为止，已有超过78个HSP位点被定位为HSP的病因。然而，中国HSP患者的临床和突变谱仍不清楚。在这项研究中，我们的目标是对中国HSP患者的临床表型和遗传分布进行全面分析，并阐明该人群的主要发病机制。方法首先对99例患者的149个HSP相关基因进行新一代测序。在无已知致病基因突变的患者中进一步进行多重结扎依赖探针扩增检测。我们同时对其他中国队列中报告的HSP患者进行了回顾性研究。对上述两组中国HSP患者的临床和分子特征进行分析和总结。最后，我们在体外进一步验证了两种主要痉挛性截瘫（SPG）患者（SPG4和SPG11）成纤维细胞的细胞变化。结果ADHSP以单纯型为主（94%），ARHSP以复杂型为主（78%）。在ADHSP中，我们发现SPG4（79%）最为普遍，其次是SPG3A（11%）、SPG6（4%）和SPG33（2%）。微小突变是SPG4患者常见的遗传原因，大多数突变位于spastin蛋白的AAA盒结构域。在ARHSP中，最常见的亚型是SPG11(53%)，其次是SPG5（32%）、SPG35（6%）和SPG46（3%）。单倍型分析显示，携带c.334C > T （p.R112*）突变incyp7b1基因的14个家族共有一个独特的单倍型，提示始创者效应。在功能上，我们观察到SPG4成纤维细胞线粒体动力学和网络模式显著不同，线粒体膜电位降低（Δψm），活性氧增加，ATP含量降低。此外，我们还发现了SPG11成纤维细胞中lamp1阳性细胞器的扩大和自溶酶体的异常积累。结论sour研究提供了中国HSP的全面临床谱和遗传图谱。我们还提供了线粒体和自溶酶体介导的热休克发病途径的额外证据。
BackgroundHereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population.MethodsWe firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro.ResultsMost patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation inCYP7B1gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts.ConclusionsOur study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP.
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影响因子：
4.3
作者：
Abrahamsen G;Fan Y;Matigian N;Wali G;Bellette B;Sutharsan R;Raju J;Wood SA;Veivers D;Sue CM;Mackay-Sim A
通讯作者：
Mackay-Sim A
影响因子：
11.2
作者：
Mishra, Himanshu K.;Prots, Iryna;Havlicek, Steven;Kohl, Zacharias;Perez-Branguli, Francesc;Boerstler, Tom;Anneser, Lukas;Minakaki, Georgia;Wend, Holger;Hampl, Martin;Leone, Marina;Brueckner, Martina;Klucken, Jochen;Reis, Andre;Boyer, Leah;Schuierer, Gerhard;Behrens, Juergen;Lampert, Angelika;Engel, Felix B.;Gage, Fred H.;Winkler, Juergen;Winner, Beate
通讯作者：
Winner, Beate
影响因子：
5.2
作者：
Denton, Kyle R.;Lei, Ling;Grenier, Jeremy;Rodionov, Vladimir;Blackstone, Craig;Li, Xue-Jun
通讯作者：
Li, Xue-Jun
影响因子：
3.8
作者：
Blair, Marcia A.;Riddle, Megan E.;Hedera, Peter
通讯作者：
Hedera, Peter
影响因子：
12.4
作者：
Connolly NMC;Theurey P;Adam-Vizi V;Bazan NG;Bernardi P;Bolaños JP;Culmsee C;Dawson VL;Deshmukh M;Duchen MR;Düssmann H;Fiskum G;Galindo MF;Hardingham GE;Hardwick JM;Jekabsons MB;Jonas EA;Jordán J;Lipton SA;Manfredi G;Mattson MP;McLaughlin B;Methner A;Murphy AN;Murphy MP;Nicholls DG;Polster BM;Pozzan T;Rizzuto R;Satrústegui J;Slack RS;Swanson RA;Swerdlow RH;Will Y;Ying Z;Joselin A;Gioran A;Moreira Pinho C;Watters O;Salvucci M;Llorente-Folch I;Park DS;Bano D;Ankarcrona M;Pizzo P;Prehn JHM
通讯作者：
Prehn JHM