Lamin AC mutations and heart: Nuclear envelope damage or disruption of transcription?

Abstract

Mutations in the LMNA gene, which encodes the nuclear lamin A/C protein, are implicated in the pathogenesis of over ten phenotypically diverse diseases, including dilated cardiomyopathy (DCM). Two hypotheses have been proposed to explain the tissue specificity of LMNA mutations: 1) Nuclear fragility which may affect to a greater extent mechanically stressed tissues such as cardiac muscle (structural hypothesis); and 2) dysregulation of gene transcription. The objective of this study was to determine which hypothesis explains how LMNA mutations cause DCM. In our cohort of 25 DCM patients, 34% displayed cardiomyocytes with nuclear abnormalities, however, point mutations or large deletions of the lamin A/C gene were found in both patients with or without nuclear envelope damage. Moreover, some DCM patients with nuclear damage were free of lamin A/C gene somatic mutation. These results provide support for the structural hypothesis, but do not exclude the hypothesis of dysregulation of gene transcription. To test the latter hypothesis, we used cellular models expressing lamin A/C mutant proteins. We showed that, although the distributions of some proteins known to be involved in transcription regulation, such as SUMO1 or Ubc9 are disturbed, lamin A/C mutants have no significant effect on transcriptional activity of GATA-4 and MEF2C, two sumoylated transcription factors involved in cardiac gene transcription. In conclusion, we confirmed that structural hypothesis plays a role in DCM pathogenesis, however at this point, the gene-regulation hypothesis can not be excluded. We showed for the first time that a large deletion encompassing several exons of the LMNA gene and leading to a marked reduction of lamin A/C proteins in cardiac tissue, and thus to haploinsufficiency, is a new molecular mechanism associated with dilated cardiomyopathy.