Smad signaling in skeletal muscle laminopathies

《科学文摘》 编码Lamins的人类LMNA基因突变会导致骨骼肌营养不良 表现出广泛的疾病严重性，即使在拥有相同 突变。这一观察结果暗示了修饰基因的作用。确定候选修改量 对一个患有LMNA的家系成员进行了基因全基因组测序 Emery-Dreifuss肌营养不良症(EDMD2)(c.1580G和gt；C；p.R527P)。分析显示， Smad7基因的新变异(c.932A.G；p.Q311R)，与疾病严重程度分离。 Smad7编码一种保守的转化生长因子-β/Smad信号通路的抑制因子。激活此选项 Smad7水平降低导致的抑制肌肉生长和分化的途径及其原因 肌肉组织动态平衡的丧失。利用果蝇的LMNA肌营养不良症模型，我们 发现过度表达Smad7的果蝇直系同源物抑制了导致的致死性 被变异的羔羊。检验Smad信号改变肌肉表型的假设 由突变的lamins诱导，我们将1)改变Smad信号并检测对肌肉的影响 果蝇LMNA肌肉病模型的表型和2)对另一个模型进行WGS LMNA突变家系，其成员表现为严重或无症状的肌肉 疾病表型。此外，我们还将分析肌肉活检组织中的转化生长因子-β/smad信号。 来自患有LMNA肌营养不良症的人。总的来说，我们的实验将决定 转化生长因子-β/Smad信号与层蛋白在骨骼肌疾病中的相互作用及鉴定 候选修饰基因是潜在的治疗靶点。我们的发现有可能 广泛的影响，因为患有LMNA肌肉疾病的人有常见疾病的症状 比如糖尿病和代谢综合征。

Scientific Abstract Mutations in the human LMNA gene encoding lamins cause skeletal muscular dystrophy that exhibits a wide range of disease severity, even among family members possessing the identical mutation. This observation suggests the action of modifier genes. To identify candidate modifier genes, whole genome sequencing (WGS) was performed on members of a family with LMNA Emery-Dreifuss muscular dystrophy (EDMD2) (c.1580G>C; p.R527P). The analysis revealed a novel variant in the SMAD7 gene (c.932A.G; p.Q311R) that segregated with disease severity. SMAD7 encodes an inhibitor of the conserved TGF-β/Smad signaling pathway. Activation of this pathway due to reduced levels of SMAD7 represses muscle growth and differentiation and causes loss of muscle tissue homeostasis. Using a Drosophila model of LMNA muscular dystrophy, we found that over-expression of the Drosophila orthologue of SMAD7 suppressed lethality caused by mutant lamins. To test the hypothesis that Smad signaling modifies muscle phenotypes induced by mutant lamins, we will 1) alter Smad signaling and assay for effects on muscle phenotypes in Drosophila models of LMNA muscle disease and 2) perform WGS on another family with an LMNA mutation in which members exhibit either severe or asymptomatic muscle disease phenotypes. In addition, we will analyze TGF-β/Smad signaling in muscle biopsy tissue from individuals with LMNA muscular dystrophy. Collectively, our experiments will determine the interplay between TGF-β/Smad signaling and lamins in skeletal muscle disease and identify candidate modifier genes are potential targets for therapy. Our discoveries have the potential for broad impact as individuals with LMNA muscle disease have symptoms of common diseases such as diabetes and metabolic syndrome.