Quantitative expression of the mutated lamin A/C gene in patients with cardiolaminopathy

Objectives The authors sought to investigate the gene and protein expression in Lamin A/C (LMNA)-mutated dilated cardio-laminopathy (DCM) patients (DCMLMNAMut) versus LMNA-wild-type DCM (DCMLMNAWT), and normal controls (CTRLLMNAWT). 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 Delta Delta CT 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 DCMLMNAWT patients and CTRLLMNAWT 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 DCMLMNAMut versus DCMLMNAWT versus normal hearts (CTRLLMNAWT). Results LMNA was significantly underexpressed in mRNA from peripheral blood and myocardium of DCMLMNAMut patients versus DCMLMNAWT and CTRLLMNAWT. In 311 individuals, blind to genotype, the QGELMNA 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 DCMLMNAMut 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.