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 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. [Copyright &y& Elsevier]