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Mutations in the LMNA gene result in at least 15 distinct disorders ranging from muscular dystrophies to neurological disorders to lipodystrophies. These disorders are collectively called laminopathies. Lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. One outstanding question is how mutations in the Lamin genes result in such different disorders, as these proteins play a critical role in nuclear shape and are expressed in most cell types. Interestingly, mutant forms of lamin proteins aggregate, which may be toxic to the cells. Studies on the fruit fly Drosophila melanogaster has been instrumental in our understanding of la min functions. Flies have two lamin genes, LamC and Lam Dm0, that evolved from a single ancestral gene and are homologous to both the LamA/C and LamB genes in humans. Many of the disease causing mutations in LMNA are conserved in both LamC and Lam Dm0. Fur thermore, while LamC is not expressed in neurons, Lam Dm0 is expressed in both muscle and neurons suggesting that Lam Dm0 in muscles and neurons has both Aand Btype lamin activities. Therefore, we hypothesize that certain tissues are susceptible to spe cific lamin mutations due to the inability of tissue specific quality control mechanisms to degrade those mutant forms, leading to protein aggregation and cellular toxicity. We have found that the p38Kb interacts with the CASA complex in flies to regulate the degradation of Lam Dm0. However, we will be testing if different lamin mutations aggregates in muscles and neurons.
Acquah, Bismark, "MUTATIONS IN LAMIN GENE AND HOW IT CAUSES MULTIPLE TISSUE-SPECIFIC DISORDERS" (2022). University Research Symposium. 395.