Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants

Abstract

Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype–phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.

Genomic analysis of a novel pathogenic variant in the gene LMNA associated with cardiac laminopathies found in Ecuadorian siblings: A case report

“…Moreover, mutations in the LMNA gene result in severe nuclear abnormalities and a higher risk of thromboembolic complications ( 18 , 19 ). Patients carrying LMNA mutations present more aggressive laminopathies and have higher rates of life-threatening arrhythmias and end-stage heart failure ( 21 – 23 ).…”

Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431*) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys)

“…Few studies have made quantitative measurements of nuclear morphology in DCM patients bearing LMNA mutations. Ferradini et al (2021) [ 11 ] reported increased area and elongation but decreased circularity in leukocyte nuclei from DCM patients bearing LMNA missense mutations (Arg189Gln and Glu317Lys). Consistently, our DCM patient with the Ser431* mutation also showed nuclei with decreased circularity and increased elongation; however, in contrast with the report in missense mutations, nuclear area measurements were higher than in wild-type nuclei ( p < 0.001).…”

“…The hallmark of laminopathies is the presence of nuclear abnormalities in different cell types, including blebs, herniations, and honeycomb-structures [ 9 ]. Leukocytes are one of several cell types that show nuclear morphology alterations in DCM patients with LMNA mutations [ 10 , 11 ]. However, the molecular mechanisms are not fully understood and are most likely explained by a combination of functional effects that are cell/tissue-specific [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations

“…We broaden the understanding of interdisease phenotypic variability here by characterizing the global proteomic changes from heterozygous overexpression (mutant and WT) of a nonaggregating (E317 K) 19,20 and two aggregating lamin A mutations (N195 K and Q353 K). 4,21,22 We discovered that there was very little overlap in differentially expressed proteins (DEPs) between any of the mutations; many of which play important roles in cardiac function.…”