Mutations in Lamin A/C and their binding partners and nuclear envelope phenotype in cardiomyocytes from Dilated cardiomoyopathy patients

Abstract

Lamin A/C gene is one of most frequently reported mutated genes in dilated cardiomyopathy which is characterized by the dilatation of cardiac chambers and impaired contraction. Lamin A and C are major components of the nuclear lamina. From a cohort of DCM patients, we selected seven patients displaying major cardiomyocytes nucleus envelope abnormalities on electron microscopy images. In the DNA from these patients, we screened both Lamin A/C and thymopoietin genes for mutations by direct sequencing. Thymopoietin is the only lamin A/C binding partner previously shown to harbor a mutation in a DCM patient. Only one of these seven patients carried a mutation in the lamin A/C gene. No patient carried a mutation in the thymopoietin gene. In our control population of DCM patients with normal ultrastructural phenotype, two patients bore a lamin A/C gene mutation; none had a mutation in the thymopoietin gene. Taken together, our results suggest that patients with a clinical suspicion of lamin A/C mutation and with marked abnormality of cardiomyocytes nuclei might be free of both lamin A/C and thymopoietin germline mutation. These patients may therefore carry a mutation in another gene encoding a protein involved in the maintenance of the nuclear architecture or a somatic mutation. Furthermore, the occurrence of mutation in one of these genes does not necessary lead to cardiomyocyte nuclear envelope defects.

A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation

“…Minor nuclear defects are a normal feature of nucleated cells. It has been shown that the amount of dysmorphic nuclei increases with age, 4 and that cardiac cells have more dysmorphic nuclei than skin fibroblasts, 25 which is also confirmed by our data [Fig. 2c(vi)].…”

“…2c(vi)]. 4 As expected, 25 for each individual the amount of dysmorphic nuclei was significantly higher in cardiac tissue than in fibroblasts. The increase itself was significantly greater for PA1 [Fig.…”

“…Interestingly, TMPO is expressed at slightly lower levels in the patient line, which is, on its own, known to be associated with the DCM in patients. 25 By contrast, SYNE2 has higher expression levels in the patient line, indicating that there are compensation mechanisms. Thus, to understand how this gene expression landscape emerges into cell and tissue phenotype, the nuclei of the cardiomyocytes were stained with DAPI and imaged via a confocal microscope (Fig.…”