The nuclear lamina consists of a meshwork of lamins that shape the nucleus and participate in various cellular processes. In humans, lamin A and C (A/C) are produced from the LMNA gene, for which more than 450 mutations have been found that result in so-called laminopathies, e.g. dilated cardiomyopathy (DCM), skeletal myopathies and premature ageing. However, the molecular basis of LMNA-associated DCM is not fully understood. In their study on page 2732, Pekka Taimen and colleagues now characterise the p.S143P mutation in LMNA, which accounts for 7% of familial DCM cases in the Finnish population. They first show that p.S143P lamin A/C localises to the nucleoplasm and forms intranuclear aggregates in fibroblasts from DCM patients with the mutation, as well as in cells transfected with p.S143P lamin A. Further analysis showed that the mutant lamin is unable to form ordered extended filament arrays in vitro, suggesting a fundamental defect in lamina assembly. Next, the authors investigated the effect of the mutation on gene expression and found genes involved in the unfolded protein response (UPR) to be upregulated. This suggests that p.S143P induces ER stress, which is known to activate the UPR. Indeed, subjecting p.S143P-expressing cells to additional ER stress led to reduced cell viability. This study thus provides new insights into the molecular basis of the pathological features of DCM and points to inhibition of ER stress as a possible future therapeutic avenue for the disease.
- © 2016. Published by The Company of Biologists Ltd