Project Summary/Abstract Nuclear envelope proteins are essential for maintaining nuclear architecture, gene expression and chromatin organization. Mutations in nuclear envelope proteins and nuclear lamins cause numerous human diseases, many of which involve in skeletal muscle defects such as Emery-Dreifuss muscular dystrophy (EDMD). Although the genetic mutations responsible for these diseases are known, the molecular mechanisms whereby perturbations in the nuclear envelope cause disease are still not well understood. Moreover, it is still unclear why mutations in ubiquitously expressed nuclear envelope proteins lead to tissue-specific pathogenesis such as striated muscle-specific defects. Our lab recently showed that the nuclear envelope transmembrane protein 39 (NET39) is a muscle-specific regulator of nuclear envelope structure and function. NET39 is downregulated in EDMD patient muscle biopsies, and deletion of Net39 in mice caused nuclear envelope deformations, congenital myopathy and juvenile lethality. Within the nuclear envelope, NET39 interacts with several components of the nuclear envelope such as LEMD2. Our studies of NET39 provide an entry point to unravel the long-standing puzzle of why striated muscle is specifically affected in nuclear envelope related diseases. We hypothesize that NET39 plays a pivotal skeletal muscle-specific role in the pathogenesis of EDMD. The overall goals of this project are to define the functions of NET39 and its interactions with other nuclear envelope proteins in regulating nuclear envelope integrity and gene expression during skeletal muscle homeostasis and disease, and to explore the role of NET39 in EDMD and other laminopathies. Ultimately, we hope to use these insights to develop new therapeutic strategies for EDMD and related laminopathies.