Cytoplasmic localization of PML particles in laminopathies.
There is growing evidence that laminopathies, diseases associated with mutations in the LMNA gene, are caused by a combination of mechanical and gene regulatory distortions. Strikingly, there is a large variability in disease symptoms between individual patients carrying an identical LMNA mutation. This is why classical genetic screens for mutations appear to have limited predictive value for disease development. Recently, the widespread occurrence of repetitive nuclear ruptures has been described in fibroblast cultures from various laminopathy patients. Since this phenomenon was strongly correlated with disease severity, the identification of biomarkers that report on these rupture events could have diagnostic relevance. One such candidate marker is the PML nuclear body, a structure that is normally confined to the nuclear interior, but leaks out of the nucleus upon nuclear rupture. Here, we show that a variety of laminopathies shows the presence of these cytoplasmic PML particles (PML CPs), and that the amount of these protein aggregates increases with severity of the disease. In addition, between clinically healthy individuals, carrying LMNA mutations, significant differences can be found. Therefore, we postulate that detection of PML CPs in patient fibroblasts could become a valuable marker for diagnosis of disease development.
Department of Molecular Cell Biology, CARIM, School for Cardiovascular Diseases, Maastricht University Medical Center, UNS50 Box 17, P.O. Box 616, NL-6200 MD, Maastricht, The Netherlands.
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F
Houben
W H
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De Vos
I P C
IP
Krapels
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M
Coorens
G J J
GJ
Kierkels
M A F
MA
Kamps
V L R M
VL
Verstraeten
C L M
CL
Marcelis
A
A
van den Wijngaard
F C S
FC
Ramaekers
J L V
JL
Broers
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D000071156:Promyelocytic Leukemia Protein; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D059008:Time-Lapse Imaging; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D015415:Biomarkers; C494847:LMNA protein, human; D034904:Lamin Type A; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human