Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.
Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.
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DOI：
10.1371/journal.pgen.1004605
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Shackleton S
中科院分区：
文献类型：
--
作者：
Meinke P;Mattioli E;Haque F;Antoku S;Columbaro M;Straatman KR;Worman HJ;Gundersen GG;Lattanzi G;Wehnert M;Shackleton S
核膜蛋白（NE）与一系列遗传性疾病有关，最常见的是肌营养不良和心肌病，如Emery-Dreifuss肌营养不良（EDMD）。EDMD在遗传和表型上都是可变的，一些修饰基因的证据已经被报道。到目前为止，已经有6个基因与EDMD有关，其中4个基因编码与连接细胞核和细胞骨架的LINC复合物相关的蛋白质。然而，50%的患者在这些基因中没有可识别的突变。使用候选方法，我们已经确定了EDMD和相关肌病患者中SUN1和SUN2基因的推定致病变异，也编码LINC复合物成分。我们的数据还表明，在其他EDMD基因共分离突变的个体中，SUN1和SUN2可以作为疾病修饰基因。5个SUN1/SUN2变异检测了成纤维细胞中受损的后核重新定位，证实了LINC复合物在核-细胞骨架偶联中的功能缺陷。此外，携带复合杂合SUN1突变的患者的肌管在核组织中表现出明显缺陷。这伴随着中心体标记物，心周蛋白，向NE募集的缺失和NE处微管成核受损，这些事件是正确的核排列所必需的。这些缺陷在表达外源性SUN1变异的C2C12肌管中重现，表明SUN1突变与核微管偶联损伤和肌核定位之间存在直接联系。我们的研究结果有力地支持了SUN1和SUN2在肌肉疾病发病机制中的重要作用，并支持了LINC复合物的缺陷通过破坏核微管结合导致肌核定位缺陷而导致疾病病理的假设。emry - dreifuss肌营养不良症（EDMD）是一种遗传性疾病，涉及肌肉萎缩和虚弱，并伴有心脏缺陷。这种疾病的严重程度和遗传原因各不相同。到目前为止，已经有6个基因与EDMD有关，其中大多数基因编码的蛋白质形成一个结构网络，支持细胞核并将其与细胞质的结构元件连接起来。这个网络在肌肉细胞中特别重要，提供对机械应变的抵抗力。该网络的减弱被认为是导致这些患者肌肉疾病发展的原因。尽管进行了严格的筛查，但至少50%的EDMD患者在6种已知基因中没有可检测到的突变。因此，我们进行了筛选并鉴定了另外两个编码核结构网络其他成分的基因SUN1和SUN2的突变。我们的发现增加了这种疾病的遗传复杂性，因为一些个体携带不止一个基因的突变。我们还表明，突变破坏细胞核和细胞质结构元件之间的连接，导致肌肉细胞中细胞核的错误定位和聚集。这种核错误定位可能是导致EDMD发病的另一个因素。
Proteins of the nuclear envelope (NE) are associated with a range of inherited disorders, most commonly involving muscular dystrophy and cardiomyopathy, as exemplified by Emery-Dreifuss muscular dystrophy (EDMD). EDMD is both genetically and phenotypically variable, and some evidence of modifier genes has been reported. Six genes have so far been linked to EDMD, four encoding proteins associated with the LINC complex that connects the nucleus to the cytoskeleton. However, 50% of patients have no identifiable mutations in these genes. Using a candidate approach, we have identified putative disease-causing variants in the SUN1 and SUN2 genes, also encoding LINC complex components, in patients with EDMD and related myopathies. Our data also suggest that SUN1 and SUN2 can act as disease modifier genes in individuals with co-segregating mutations in other EDMD genes. Five SUN1/SUN2 variants examined impaired rearward nuclear repositioning in fibroblasts, confirming defective LINC complex function in nuclear-cytoskeletal coupling. Furthermore, myotubes from a patient carrying compound heterozygous SUN1 mutations displayed gross defects in myonuclear organization. This was accompanied by loss of recruitment of centrosomal marker, pericentrin, to the NE and impaired microtubule nucleation at the NE, events that are required for correct myonuclear arrangement. These defects were recapitulated in C2C12 myotubes expressing exogenous SUN1 variants, demonstrating a direct link between SUN1 mutation and impairment of nuclear-microtubule coupling and myonuclear positioning. Our findings strongly support an important role for SUN1 and SUN2 in muscle disease pathogenesis and support the hypothesis that defects in the LINC complex contribute to disease pathology through disruption of nuclear-microtubule association, resulting in defective myonuclear positioning. Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder involving muscle wasting and weakness, accompanied by cardiac defects. The disease is variable in its severity and also in its genetic cause. So far, 6 genes have been linked to EDMD, most encoding proteins that form a structural network that supports the nucleus of the cell and connects it to structural elements of the cytoplasm. This network is particularly important in muscle cells, providing resistance to mechanical strain. Weakening of this network is thought to contribute to development of muscle disease in these patients. Despite rigorous screening, at least 50% of patients with EDMD have no detectable mutation in the 6 known genes. We therefore undertook screening and identified mutations in two additional genes that encode other components of the nuclear structural network, SUN1 and SUN2. Our findings add to the genetic complexity of this disease since some individuals carry mutations in more than one gene. We also show that the mutations disrupt connections between the nucleus and the structural elements of cytoplasm, leading to mis-positioning and clustering of nuclei in muscle cells. This nuclear mis-positioning is likely to be another factor contributing to pathogenesis of EDMD.
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影响因子：
4.4
作者：
Fidzianska, A;Hausmanowa-Petrusewicz, I
通讯作者：
Hausmanowa-Petrusewicz, I
影响因子：
37.8
作者：
Brodsky, GL;Muntoni, F;Mestroni, L
通讯作者：
Mestroni, L
影响因子：
4
作者：
Borrego-Pinto, Joana;Jegou, Thibaud;Gomes, Edgar R.
通讯作者：
Gomes, Edgar R.
影响因子：
2.7
作者：
Capanni, Cristina;Del Coco, Rosalba;Lattanzi, Giovanna
通讯作者：
Lattanzi, Giovanna
DOI：
10.4161/cc.21869
发表时间：
2012-10-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Capanni C;Squarzoni S;Cenni V;D'Apice MR;Gambineri A;Novelli G;Wehnert M;Pasquali R;Maraldi NM;Lattanzi G
通讯作者：
Lattanzi G