Quantitative expression of the mutated lamin A/C gene in patients with cardiolaminopathy.
OBJECTIVE
The authors sought to investigate the gene and protein expression in Lamin A/C (LMNA)-mutated dilated cardiolaminopathy (DCM) patients (DCM(LMNAMut)) versus LMNA-wild-type DCM (DCM(LMNAWT)), and normal controls (CTRL(LMNAWT)).


BACKGROUND
Dilated cardiolaminopathies are clinically characterized by high arrhythmogenic risk and caused by LMNA mutations. Little is known regarding quantitative gene expression (QGE) of the LMNA gene in blood and myocardium, as well as regarding myocardial expression of the lamin A/C protein.


METHODS
Using the comparative ΔΔCT method, we evaluated the QGE of LMNA (QGE(LMNA)) in peripheral blood and myocardial RNA from carriers of LMNA mutations, versus blood and myocardial samples from DCM(LMNAWT) patients and CTRL(LMNAWT) individuals. After generating reference values in normal controls, QGE(LMNA) was performed in 311 consecutive patients and relatives, blind to genotype, to assess the predictive value of QGE(LMNA) for the identification of mutation carriers. In parallel, Lamin A/C was investigated in myocardial samples from DCM(LMNAMut) versus DCM(LMNAWT) versus normal hearts (CTRL(LMNAWT)).


RESULTS
LMNA was significantly underexpressed in mRNA from peripheral blood and myocardium of DCM(LMNAMut) patients versus DCM(LMNAWT) and CTRL(LMNAWT). In 311 individuals, blind to genotype, the QGE(LMNA) showed 100% sensitivity and 87% specificity as a predictor of LMNA mutations. The receiver-operating characteristic curve analysis yielded an area under the curve of 0.957 (p < 0.001). Loss of protein in cardiomyocytes' nuclei was documented in DCM(LMNAMut) patients.


CONCLUSIONS
The reduced expression of LMNA gene in blood is a novel potential predictive biomarker for dilated cardiolaminopathies with parallel loss of protein expression in cardiomyocyte nuclei.
Centre for Inherited Cardiovascular Diseases, Foundation IRCCS Policlinico San Matteo, University of Pavia, Piazzale Golgi 19, Pavia, Italy.
Nupoor
N
Narula
Valentina
V
Favalli
Paolo
P
Tarantino
Maurizia
M
Grasso
Andrea
A
Pilotto
Riccardo
R
Bellazzi
Alessandra
A
Serio
Fabiana I
FI
Gambarin
Philippe
P
Charron
Benjamin
B
Meder
Yigal
Y
Pinto
Perry M
PM
Elliott
Jens
J
Mogensen
Martino
M
Bolognesi
Michela
M
Bollati
Eloisa
E
Arbustini
D015415:Biomarkers / Q000097:blood; D002311:Cardiomyopathy, Dilated / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D015415:Biomarkers; C494847:LMNA protein, human; D034904:Lamin Type A; D012333:RNA, Messenger