Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers.
Nuclear envelope-related muscular dystrophies, in particular those referred to as laminopathies, are relatively novel and unclear diseases, also considering the increasing number of mutations identified so far in genes of the nuclear envelope. As regard LMNA gene, only tentative relations between phenotype, type and localization of the mutations have been established in striated muscle diseases, while laminopathies affecting adipose tissue, peripheral nerves or progerioid syndromes could be linked to specific genetic variants. This study describes the biochemical phenotype of neuromuscular laminopathies in samples derived from LMNA mutant patients. Since it has been reported that nuclear alterations, due to LMNA defects, are present also in fibroblasts from Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy patients, we analyzed 2D-maps of skin fibroblasts of patients carrying 12 different LMNA mutations spread along the entire gene. To recognize distinctive proteins underlying affected biochemical pathways, we compared them with fibroblasts from healthy controls and, more importantly, fibroblasts from patients with non-lamin related neuromuscular disorders. We found less abundance of cytoskeletal/structural proteins, confirming a dominant role for Lamin A/C in structural support of nuclear architecture. Interestingly, we also established significant changes in the expression of proteins involved in cellular energy production and oxidative stress response. To our knowledge, this is the first report where proteomics was applied to characterize ex-vivo cells from LMNA patients, suggesting that this may represent a new approach to better understand the molecular mechanisms of these rare diseases and facilitate the development of novel therapeutic treatments.
ProMiFa, Protein Microsequencing Facility, Division of Cell Biology and Genetics, San Raffaele Scientific Institute, Milan, Italy.
Cinzia
C
Magagnotti
Angela
A
Bachi
Gianpaolo
G
Zerbini
Elena
E
Fattore
Isabella
I
Fermo
Michela
M
Riba
Stefano C
SC
Previtali
Maurizio
M
Ferrari
Annapaola
A
Andolfo
Sara
S
Benedetti
D000328:Adult; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D040081:Protein Array Analysis; D040901:Proteomics; D012867:Skin / Q000166:cytology / Q000378:metabolism
D003598:Cytoskeletal Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins