부산대학교 도서관

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development. Author summary: Muscular dystrophy is a progressive muscle-wasting disorder that eventually leads to cardiac disease. Mutations in the LMNA gene, which encodes an intermediate filament protein involved in the structure and organization of the nucleus, is a common but poorly understood cause of this disease. How variants across the breadth of LMNA contribute to mechanistic cellular defects that lead to disease is poorly understood, leading to hurdles in diagnosing disease and developing treatments. We found that by introducing amino acid substitutions found in patients with striated muscle disorders caused by LMNA into the conserved lmn-1 gene of the nematode C. elegans, we could rapidly test the function of these variants to better understand their roles. We found that variants modeling diseases that involve both skeletal and cardiac muscle in humans were the most pathogenic in C. elegans, typically affecting both viability and movement, while those that modeled cardiac disease alone had less deleterious effects in C. elegans. Thus, our new C. elegans models can be used to diagnose and predict the severity of new variants of human LMNA as well as better understanding the molecular mechanisms of lamins in normal development. [ABSTRACT FROM AUTHOR]