Lamin A/C deficiency leads to defective nuclear mechanics and impaired mechanotransduction. Mutations in the lamin A/C gene (LMNA) cause various human diseases, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. Lamin A/C is a structural component of the nuclear lamina, which determines nuclear shape and size. It also plays a role in organizing nuclear pore complexes and recruiting other proteins to the nuclear envelope. Two types of lamins are found in mammalian cells: A-type lamins (lamin A, C, AΔ10, and C2) and B-type lamins (B1 and B2/B3). Mutations in the gene encoding A-type lamins and their binding partners have been associated with various human diseases. Lamin A/C deficiency is associated with defective nuclear mechanics and impaired mechanically activated gene transcription. Lmna^-/- mice develop severe muscle wasting and contractures similar to Emery-Dreifuss muscular dystrophy by 3–4 weeks and die by 8 weeks. Cells derived from Lmna^-/- mice have misshapen nuclei and obvious ultrastructural damage. Distorted nuclear shape has also been demonstrated in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene and in cells from Caenorhabditis elegans with reduced lamin levels. Nuclear mechanics in cells from Lmna^-/- mice are defective, with Lmna^-/- nuclei displaying increased deformation and fragility under strain. Transcriptional activation in response to mechanical stimuli is attenuated in Lmna^-/- cells, impairing viability of mechanically strained cells. These data suggest that the structural and gene regulation hypotheses of the laminopathies are closely related, and different mutations may cause specific phenotypes by differentially affecting these processes. Lamin A/C deficiency leads to decreased nuclear stiffness and altered nuclear mechanics. The observed increased nuclear deformation in lamin-deficient cells is unlikely to be due to altered force transmission to the nucleus. The softer cytoskeleton would result in an underestimation of the nuclear stiffness. Lamin A/C-deficient cells have decreased nuclear stiffness and altered nuclear mechanics. Strain-induced damage to the more fragile nucleus could provide one explanation for tissue-specific effects of lamin A/C mutations. To examine nuclear envelope integrity, fluorescently labeled 70-kDa dextran was microinjected into either the cytoplasm or nucleus of adherent fibroblasts. Cytoplasmic injection revealed that the high-molecular-weight dextran was excluded from the nucleus in both WT and lamin-deficient cells, indicating that nuclear integrity is not significantly impaired in Lmna^-/- cells under resting conditions. The increased fraction of apoptotic cells in mechanically strained Lmna^-/- fibroblasts indicates that necrosis through nuclear ruptureLamin A/C deficiency leads to defective nuclear mechanics and impaired mechanotransduction. Mutations in the lamin A/C gene (LMNA) cause various human diseases, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. Lamin A/C is a structural component of the nuclear lamina, which determines nuclear shape and size. It also plays a role in organizing nuclear pore complexes and recruiting other proteins to the nuclear envelope. Two types of lamins are found in mammalian cells: A-type lamins (lamin A, C, AΔ10, and C2) and B-type lamins (B1 and B2/B3). Mutations in the gene encoding A-type lamins and their binding partners have been associated with various human diseases. Lamin A/C deficiency is associated with defective nuclear mechanics and impaired mechanically activated gene transcription. Lmna^-/- mice develop severe muscle wasting and contractures similar to Emery-Dreifuss muscular dystrophy by 3–4 weeks and die by 8 weeks. Cells derived from Lmna^-/- mice have misshapen nuclei and obvious ultrastructural damage. Distorted nuclear shape has also been demonstrated in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene and in cells from Caenorhabditis elegans with reduced lamin levels. Nuclear mechanics in cells from Lmna^-/- mice are defective, with Lmna^-/- nuclei displaying increased deformation and fragility under strain. Transcriptional activation in response to mechanical stimuli is attenuated in Lmna^-/- cells, impairing viability of mechanically strained cells. These data suggest that the structural and gene regulation hypotheses of the laminopathies are closely related, and different mutations may cause specific phenotypes by differentially affecting these processes. Lamin A/C deficiency leads to decreased nuclear stiffness and altered nuclear mechanics. The observed increased nuclear deformation in lamin-deficient cells is unlikely to be due to altered force transmission to the nucleus. The softer cytoskeleton would result in an underestimation of the nuclear stiffness. Lamin A/C-deficient cells have decreased nuclear stiffness and altered nuclear mechanics. Strain-induced damage to the more fragile nucleus could provide one explanation for tissue-specific effects of lamin A/C mutations. To examine nuclear envelope integrity, fluorescently labeled 70-kDa dextran was microinjected into either the cytoplasm or nucleus of adherent fibroblasts. Cytoplasmic injection revealed that the high-molecular-weight dextran was excluded from the nucleus in both WT and lamin-deficient cells, indicating that nuclear integrity is not significantly impaired in Lmna^-/- cells under resting conditions. The increased fraction of apoptotic cells in mechanically strained Lmna^-/- fibroblasts indicates that necrosis through nuclear rupture