Submitted by Clark Pinyan, MD
ASC-1 is a Cell Cycle Regulator Associated With Severe and Mild Forms of Myopathy
Villar-Quiles RN, et al. Ann Neurol 2020;87:217-232
Dysfunction of the transcriptional coactivator ASC-1 (activating signal cointegrator 1) complex has been demonstrated in forms of ALS, SMA, and congenital myopathies. Mutations in TRIP4 gene, which encodes ASC-1, has been described recently in a family with congenital myopathy. This study assesses 5 different families with 7 novel TRIP4 mutations. All mutations caused ASC-1 depletion. Clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers and / or mild endomysial fibrosis. ASC-1 depletion in CSC12 and patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of celll cycle proteins, and /or shortening of the G0/G1 cell cycle phase leading to cell size reduction.
There is increasing recognition that ASC complex and other transcriptional modulators are important in pathological processes whether acquired or inherited. Defining the range of disease associated with defects in this gene may lead to understanding the final common pathologic mechanisms and potential interventions.