Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption.
Major nuclear envelope abnormalities, such as disruption and/or presence of intranuclear organelles, have rarely been described in cardiomyocytes from dilated cardiomyopathy (DCM) patients. In this study, we screened a series of 25 unrelated DCM patient samples for (a) cardiomyocyte nuclear abnormalities and (b) mutations in LMNA and TMPO as they are two DCM-causing genes that encode proteins involved in maintaining nuclear envelope architecture. Among the 25 heart samples investigated, we identified major cardiomyocyte nuclear abnormalities in 8 patients. Direct sequencing allowed the detection of three heterozygous LMNA mutations (p.D192G, p.Q353K and p.R541S) in three patients. By multiplex ligation-dependant probe amplification (MLPA)/quantitative real-time PCR, we found a heterozygous deletion encompassing exons 3-12 of the LMNA gene in one patient. Immunostaining demonstrated that this deletion led to a decrease in lamin A/C expression in cardiomyocytes from this patient. This LMNA deletion as well as the p.D192G mutation was found in patients displaying major cardiomyocyte nuclear envelope abnormalities, while the p.Q353K and p.R541S mutations were found in patients without specific nuclear envelope abnormalities. None of the DCM patients included in the study carried a mutation in the TMPO gene. Taken together, we found no evidence of a genotype-phenotype relationship between the onset and the severity of DCM, the presence of nuclear abnormalities and the presence or absence of LMNA mutations. We demonstrated that a large deletion in LMNA associated with reduced levels of the protein in the nuclear envelope suggesting a haploinsufficiency mechanism can lead to cardiomyocyte nuclear envelope disruption and thus underlie the pathogenesis of DCM.
Gupta
Pallavi
P
Faculty of Health Sciences, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
Bilinska
Zofia T
ZT
Sylvius
Nicolas
N
Boudreau
Emilie
E
Veinot
John P
JP
Labib
Sarah
S
Bolongo
Pierrette M
PM
Hamza
Akil
A
Jackson
Tracy
T
Ploski
Rafal
R
Walski
Michal
M
Grzybowski
Jacek
J
Walczak
Ewa
E
Religa
Grzegorz
G
Fidzianska
Anna
A
Tesson
Frédérique
F
D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000648:ultrastructure*; D009685:Nuclear Envelope / Q000648:ultrastructure*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
D004268:DNA-Binding Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2