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Our goal was to define ASC\u20101 neuromuscular function and the phenotypical spectrum associated with TRIP4<\/jats:italic> mutations.<\/jats:p><\/jats:sec>Methods<\/jats:title>Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4<\/jats:italic> mutations. Fluorescence activated cell sorting and Western blot were performed in patient\u2010derived fibroblasts and muscles and in Trip4<\/jats:italic> knocked\u2010down C2C12 cells.<\/jats:p><\/jats:sec>Results<\/jats:title>All mutations caused ASC\u20101 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and\/or mild endomysial fibrosis. ASC\u20101 depletion in C2C12 and in patient\u2010derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and\/or shortening of the G0\/G1 cell cycle phase leading to cell size reduction.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Our results expand the phenotypical and molecular spectrum of TRIP4<\/jats:italic>\u2010associated disease to include mild adult forms with or without cardiomyopathy, associate ASC\u20101 depletion with isolated primary muscle involvement, and establish TRIP4<\/jats:italic> as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic\u2010body myopathies. They also identify ASC\u20101 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. 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