Smad signaling in skeletal muscle laminopathies

科学文摘 编码核纤层蛋白的人类 LMNA 基因突变会导致骨骼肌营养不良症 表现出广泛的疾病严重程度，即使在拥有相同疾病的家庭成员中也是如此 突变。这一观察表明修饰基因的作用。识别候选修饰符 基因，对患有 LMNA 的家庭成员进行全基因组测序 (WGS) Emery-Dreifuss 肌营养不良症 (EDMD2) (c.1580G>C；p.R527P)。分析揭示了一个 SMAD7 基因（c.932A.G；p.Q311R）中的新变体随疾病严重程度而分离。 SMAD7 编码保守的 TGF-β/Smad 信号通路的抑制剂。激活这个 由于 SMAD7 水平降低而抑制肌肉生长和分化的途径 肌肉组织稳态丧失。使用 LMNA 肌营养不良症的果蝇模型，我们 发现 SMAD7 果蝇直系同源物的过度表达抑制了致死率 由突变核纤层蛋白。检验 Smad 信号传导改变肌肉表型的假设 由突变核纤层蛋白诱导，我们将 1) 改变 Smad 信号传导和对肌肉影响的测定 LMNA 肌肉疾病果蝇模型的表型，2) 对另一个进行全基因组测序 (WGS) 具有 LMNA 突变的家庭，其中成员表现出严重或无症状的肌肉 疾病表型。此外，我们将分析肌肉活检组织中的 TGF-β/Smad 信号传导 来自 LMNA 肌营养不良症患者。总的来说，我们的实验将确定 骨骼肌疾病中 TGF-β/Smad 信号传导与核纤层蛋白之间的相互作用并鉴定 候选修饰基因是潜在的治疗靶标。我们的发现有潜力 LMNA 肌肉疾病患者具有常见疾病的症状，因此影响广泛 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.