Smad signaling in skeletal muscle laminopathies

科学抽象 编码核纤层蛋白的人LMNA基因的突变引起骨骼肌营养不良， 表现出广泛的疾病严重程度，即使在家庭成员拥有相同的 突变这一观察结果表明了修饰基因的作用。识别候选修改量 基因，全基因组测序（WGS）进行了一个家庭的成员与LMNA Emery-Dreifuss肌营养不良症（EDMD 2）（c.1580G>C; p.R527P）。分析显示， SMAD 7基因（c.932A.G; p.Q311R）中的新变体，其随疾病严重程度分离。 SMAD 7编码保守的TGF-β/Smad信号通路的抑制剂。激活此 由于SMAD 7水平降低导致的途径抑制肌肉生长和分化， 肌肉组织失去平衡使用LMNA肌营养不良症的果蝇模型，我们 发现过表达SMAD 7的果蝇直向同源物抑制致死性， 突变核纤层蛋白为了验证Smad信号改变肌肉表型的假设， 通过突变核纤层蛋白诱导，我们将1）改变Smad信号传导并测定对肌肉的影响 表型的果蝇模型的LMNA肌肉疾病和2）进行WGS对另一个 一个LMNA突变的家族，其中成员表现出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TGF-β/Smad信号传导， 来自患有LMNA肌营养不良症的个体。总的来说，我们的实验将决定 TGF-β/Smad信号通路与层粘连蛋白在骨骼肌疾病中相互作用及其鉴定 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肌肉疾病的个体具有常见疾病的症状 例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.