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bioRxiv · 10.1101/2020.10.20.347088

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

Medalia, O.·Kronenberg-Tenga, R.·Tatli, M.·Eibauer, M.·Wu, W.·Shin, J.-Y.·Bonne, G.·Worman, H. J.
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Abstract

The LMNA gene encodes the A-type lamins that polymerize into ~3.5 nm thick filaments, and together with B-type lamins and lamin binding proteins form the nuclear lamina. Mutations in LMNA are associated with a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from LmnaH222P/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 LmnaH222P/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.

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Medalia, O., Kronenberg-Tenga, R., Tatli, M., Eibauer, M., Wu, W., Shin, J.-Y., Bonne, G., Worman, H. J.. 2020-10-20. A lamin A/C variant causing striated muscle disease provides insights into filament organization. https://doi.org/10.1101/2020.10.20.347088

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