title: Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption.
abstract: 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.
authors.affiliation: Faculty of Health Sciences, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gupta
authors.forename: Zofia T
authors.initials: ZT
authors.lastname: Bilinska
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sylvius
authors.forename: Emilie
authors.initials: E
authors.lastname: Boudreau
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: Sarah
authors.initials: S
authors.lastname: Labib
authors.forename: Pierrette M
authors.initials: PM
authors.lastname: Bolongo
authors.forename: Akil
authors.initials: A
authors.lastname: Hamza
authors.forename: Tracy
authors.initials: T
authors.lastname: Jackson
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.forename: Michal
authors.initials: M
authors.lastname: Walski
authors.forename: Jacek
authors.initials: J
authors.lastname: Grzybowski
authors.forename: Ewa
authors.initials: E
authors.lastname: Walczak
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Religa
authors.forename: Anna
authors.initials: A
authors.lastname: Fidzianska
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tesson
mesh_terms: 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
chemical_list: D004268:DNA-Binding Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2