A lamin A/C variant causing striated muscle disease provides insights into filament organization.

Rafael Kronenberg-Tenga, Meltem Tatli, Matthias Eibauer, Wei Wu, Ji-Yeon Shin, Gisèle Bonne, Howard J Worman, Ohad Medalia

Journal of cell science 2021 Mar 22

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The LMNA gene encodes the A-type lamins, which polymerize into ∼3.5-nm-thick filaments and, together with B-type lamins and associated proteins, form the nuclear lamina. Mutations in LMNA cause a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from Lmna H222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filaments in situ and using a nuclear extraction protocol. Averaging of individual segments of filaments in Lmna H222P/H222P mouse fibroblasts resolved two polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure. © 2021. Published by The Company of Biologists Ltd.

Citation

Rafael Kronenberg-Tenga, Meltem Tatli, Matthias Eibauer, Wei Wu, Ji-Yeon Shin, Gisèle Bonne, Howard J Worman, Ohad Medalia. A lamin A/C variant causing striated muscle disease provides insights into filament organization. Journal of cell science. 2021 Mar 22;134(6)