Abstract
LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.
Highlights
In eukaryotic cells, DNA is separated from the cytoplasm by the nuclear envelope (NE)
Apart from nonsense mutations that have not been reported in LMNA-related congenital muscular dystrophies (L-CMD), all kinds of mutations are observed in Emery–Dreifuss muscular dystrophy (EDMD) and L-CMD
Laminopathies correspond to a highly heterogeneous group of disorders affecting either tissues in an isolated fashion or with a systemic involvement mainly observed in premature ageing syndromes and overlapping laminopathies [15,16]
Summary
DNA is separated from the cytoplasm by the nuclear envelope (NE). The NE is composed of two lipid bilayers: the outer nuclear membrane (ONM) facing the cytoplasm and directly connected to the endoplasmic reticulum, and the inner nuclear membrane (INM) facing DNA. The. INM and the ONM are interconnected at the nuclear pores, allowing for the shuttling of proteins. Cells 2020, 9, 844 and RNAs between the nucleus and the cytoplasm. The INM is characterized by a subset of integral membrane proteins termed nuclear envelope transmembrane proteins (NETs) [1]. Underneath the INM is the nuclear lamina, composed of A- and B-type Lamins. The LMNA gene encodes for Lamin A and Lamin C, whereas LMNB1 and LMNB2 encode for Lamin B1 and Lamin B2, respectively.
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