Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients.
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.
Mitsuhashi
Hiroaki
H
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
Hayashi
Yukiko K
YK
Matsuda
Chie
C
Noguchi
Satoru
S
Wakatsuki
Shuji
S
Araki
Toshiyuki
T
Nishino
Ichizo
I
D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014162:Transfection
C494847:LMNA protein, human; D034904:Lamin Type A