Abstract
ABSTRACTLaminopathies yield tissue-specific pathologies, yet arise from mutation of ubiquitously-expressed genes. A little investigated hypothesis to explain this is that the mutated proteins or their partners have tissue-specific splice variants. To test this, we analyzed RNA-Seq datasets, finding novel isoforms or isoform tissue-specificity for: Lap2, linked to cardiomyopathy; Nesprin 2, linked to Emery-Dreifuss muscular dystrophy and Lmo7, that regulates the Emery-Dreifuss muscular dystrophy linked emerin gene. Interestingly, the muscle-specific Lmo7 exon is rich in serine phosphorylation motifs, suggesting regulatory function. Muscle-specific splice variants in non-nuclear envelope proteins linked to other muscular dystrophies were also found. Nucleoporins tissue-specific variants were found for Nup54, Nup133, Nup153 and Nup358/RanBP2. RT-PCR confirmed novel Lmo7 and RanBP2 variants and specific knockdown of the Lmo7 variantreduced myogenic index. Nuclear envelope proteins were enriched for tissue-specific splice variants compared to the rest of the genome, suggesting that splice variants contribute to its tissue-specific functions.
Highlights
Nuclear envelope (NE) links to inherited disease yielded the conundrum of how mutations in widely expressed proteins can yield many distinct pathologies, each focused in different tissues [1]
This is generally attributed to non-unique sequences or unknown, or not searched for, post-translational modifications, but it could be explained by tissue-specific splice variants that are not annotated in the databases so that the sequences are not searched for in the mass spectrometry analysis
While 183 unique junctionspanning peptides were identified, none of these turned out to be novel, due to poor rat genome annotations and this number reflects only a small fraction of the splice variants predicted from the RNA-Seq data
Summary
Nuclear envelope (NE) links to inherited disease yielded the conundrum of how mutations in widely expressed proteins can yield many distinct pathologies, each focused in different tissues [1]. The NE is a double membrane system comprised of inner (INM) and outer (ONM) nuclear membranes and associated proteins that must integrate all communication between the nucleus and the rest of the cell and tissue. Nucleotides, and small molecules through the NE is directed by the nuclear pore complexes (NPCs), built from >30 nucleoporin (nup) proteins together with a host of transport factors [2]. Signals can be passed through mechanotransduction [11–13], which relies on connections between cytoplasmic filament systems and the intermediate filament lamin nucleoskeleton underlying the inner surface of the INM. The primary proteins making the connections are SUN and nesprin proteins, respectively INM and ONM NE transmembrane proteins (NETs) that form the linker of nucleoskeleton and cytoskeleton (LINC) complex [14,15]. Other INM NETs directly connect to chromatin and directly participate in genome regulation [16,17]
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