Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 22, Pages 3893-3900Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.072157
Keywords
Laminopathy; A-type lamins; EDMD; LGMD1B; Akt
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Funding
- Ministry of Health, Labor and Welfare of Japan [20B-12, 20B-13]
- Japan Foundation for Neuroscience and Mental Health
- Japan Society for the Promotion of Science [21591104]
- Japanese Health Sciences Foundation
- National Institute of Biomedical Innovation (NIBIO)
- Grants-in-Aid for Scientific Research [21591104] Funding Source: KAKEN
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Mutations in LMNA, which encodes A-type nuclear lamins, cause various human diseases, including myopathy, cardiomyopathy, lipodystrophy and progeria syndrome. To date, little is known about how mutations in a single gene cause a wide variety of diseases. Here, by characterizing an antibody that specifically recognizes the phosphorylation of Ser458 of A-type lamins, we uncover findings that might contribute to our understanding of laminopathies. This antibody only reacts with nuclei in muscle biopsies from myopathy patients with mutations in the Ig-fold motif of A-type lamins. Ser458 phosphorylation is not seen in muscles from control patients or patients with any other neuromuscular diseases. In vitro analysis confirmed that only lamin A mutants associated with myopathy induce phosphorylation of Ser458, whereas lipodystrophy-or progeria-associated mutants do not. We also found that Akt1 directly phosphorylates Ser458 of lamin A with myopathy-related mutations in vitro. These results suggest that Ser458 phosphorylation of A-type lamins correlates with striated muscle laminopathies; this might be useful for the early diagnosis of LMNA-associated myopathies. We propose that disease-specific phosphorylation of A-type lamins by Akt1 contributes to myopathy caused by LMNA mutations.
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