Abstract
Mutations in the Lamin A/C gene (LMNA), which encodes A‐type nuclear Lamins, represent the most frequent genetic cause of dilated cardiomyopathy (DCM). This study is focused on a LMNA nonsense mutation (R321X) identified in several members of an Italian family that produces a truncated protein isoform, which co‐segregates with a severe form of cardiomyopathy with poor prognosis. However, no molecular mechanisms other than nonsense mediated decay of the messenger and possible haploinsufficiency were proposed to explain DCM. Aim of this study was to gain more insights into the disease‐causing mechanisms induced by the expression of R321X at cellular level. We detected the expression of R321X by Western blotting from whole lysate of a mutation carrier heart biopsy. When expressed in HEK293 cells, GFP‐ (or mCherry)‐tagged R321X mislocalized in the endoplasmic reticulum (ER) inducing the PERK‐CHOP axis of the ER stress response. Of note, confocal microscopy showed phosphorylation of PERK in sections of the mutation carrier heart biopsy. ER mislocalization of mCherry‐R321X also induced impaired ER Ca2+ handling, reduced capacitative Ca2+ entry at the plasma membrane and abnormal nuclear Ca2+ dynamics. In addition, expression of R321X by itself increased the apoptosis rate. In conclusion, R321X is the first LMNA mutant identified to date, which mislocalizes into the ER affecting cellular homeostasis mechanisms not strictly related to nuclear functions.
Highlights
Lamins are the only intermediate filaments localized in the nucleus, underlying the inner nuclear membrane [1]
The clinical features co-segregating with the R321X, collected in Table 1, were consistent with different cardiac phenotypes such as arrhythmogenic cardiomyopathy, dilated cardiomyopathy (DCM), conduction disturbances, supraventricular and ventricular arrhythmias, and sudden cardiac death (SD)
On the basis of family history and clinical features, it is most likely that the family members who suddenly died were carrying the same mutation indicating that the R321X induces a peculiar and severe form of cardiolaminopathy with a very poor prognosis
Summary
Lamins are the only intermediate filaments localized in the nucleus, underlying the inner nuclear membrane [1] They play a crucial role in maintaining cellular as well as nuclear integrity and, together with other nuclear envelope proteins, Lamins work as a scaffold for proteins that regulate DNA synthesis, responses to DNA damage, chromatin organization, gene transcription, cell cycle progression, cell differentiation and cell migration [2, 3]. Mutations in LMNA cause a group of inheritable disease phenotypes identified as Laminopathies. Most of these diseases affect the striated muscle with a persistent involvement of the heart that develops dilated cardiomyopathy (DCM), conduction system disorders (CD), and arrhythmias [5].
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