Journal article
Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling
Human molecular genetics, Vol.22(12), pp.2335-2349
06/15/2013
DOI: 10.1093/hmg/ddt079
PMCID: PMC3658163
PMID: 23427149
Abstract
Lamins are intermediate filament proteins that assemble into a meshwork underneath the inner nuclear membrane, the nuclear lamina. Mutations in the
LMNA
gene, encoding lamins A and C, cause a variety of diseases collectively called laminopathies. The disease mechanism for these diverse conditions is not well understood. Since lamins A and C are fundamental determinants of nuclear structure and stability, we tested whether defects in nuclear mechanics could contribute to the disease development, especially in laminopathies affecting mechanically stressed tissue such as muscle. Using skin fibroblasts from laminopathy patients and lamin A/C-deficient mouse embryonic fibroblasts stably expressing a broad panel of laminopathic lamin A mutations, we found that several mutations associated with muscular dystrophy and dilated cardiomyopathy resulted in more deformable nuclei; in contrast, lamin mutants responsible for diseases without muscular phenotypes did not alter nuclear deformability. We confirmed our results in intact muscle tissue, demonstrating that nuclei of transgenic
Drosophila melanogaster
muscle expressing myopathic lamin mutations deformed more under applied strain than controls.
In vivo
and
in vitro
studies indicated that the loss of nuclear stiffness resulted from impaired assembly of mutant lamins into the nuclear lamina. Although only a subset of lamin mutations associated with muscular diseases caused increased nuclear deformability, almost all mutations tested had defects in force transmission between the nucleus and cytoskeleton. In conclusion, our results indicate that although defective nuclear stability may play a role in the development of muscle diseases, other factors, such as impaired nucleo-cytoskeletal coupling, likely contribute to the muscle phenotype.
Details
- Title: Subtitle
- Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling
- Creators
- Monika Zwerger - Brigham and Women's Hospital/Harvard Medical SchoolDiana E Jaalouk - Brigham and Women's Hospital/Harvard Medical SchoolMaria L Lombardi - Brigham and Women's Hospital/Harvard Medical SchoolPhilipp Isermann - Brigham and Women's Hospital/Harvard Medical SchoolMonika Mauermann - German Cancer Research Center (DKFZ)George Dialynas - University of IowaHarald Herrmann - German Cancer Research Center (DKFZ)Lori L Wallrath - University of IowaJan Lammerding - Brigham and Women's Hospital/Harvard Medical School
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.22(12), pp.2335-2349
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/ddt079
- PMID
- 23427149
- PMCID
- PMC3658163
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 06/15/2013
- Academic Unit
- Biochemistry and Molecular Biology; University College Courses
- Record Identifier
- 9984024531802771
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