Fig. 10.
Proposed pathogenic mechanism of action of K219T-Lamin A/C in CMs. Left: healthy CMs. The SCN5A genomic region is localized in the nuclear interior and actively transcribed; the Nav1.5 sodium channel density at the plasma membrane is sufficient to assure proper impulse propagation. Right: Laminopathic CMs. Mutant Lamin A/C and PRC2 bind each other with high affinity and are enriched at the SCN5A promoter region, where the H3K27me3 (catalyzed by PRC2) and H3K9me3 repressive histone marks are also present. In this repressive environment, this genomic region is preferentially sequestered at the nuclear periphery. As a result, SCN5A gene transcription is repressed, leading to reduced expression of the Nav1.5 sodium channel at the plasma membrane, which, in turn, has an effect on reducing conduction velocity. This regulatory mechanism may be at the basis of the onset of the conduction defects in patients with LMNA-CMP