Résumé :
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Lamin A and C, encoded by LMNA gene, localize at the inner face of the nuclear membrane and interact with many proteins and DNA. Mutations reported all along the LMNA gene are responsible for multiple diseases including Emery-Dreifuss muscular dystrophy (EDMD). Among them, the deletion of the lysine 32 (_K32) leads to a severe EDMD pheontype with the first clinical signs appearing before the age of 2 and a loss of ambulation before the age of 10. The heterozygous mice carrying the _K32 mutation (Lmna_K32/+) develop a dilated cardiomyopathy (DCM) at about 30 weeks without muscle involvement. To define the earliest pathophysiological pathways involved in the development of the DCM, we perform transcriptome analysis using Illumina's mouse whole-genome expression arrays on heart from Lmna_K32/+ mice before the development of any clinical signs. The RNA samples were extracted from 10 Lmna_K32/+ and 8 wild type mice aged of 10 weeks. Statistical analysis resulted from the following workflow: quantile normalization without background subtraction, non-supervised clustering analysis and multiple comparisons test. To validate the results we performed RT-qPCR on 6 genes in relation to their change fold and their probability score. We found 30 up and 5 down-regulated genes. Their fold change ranged between -0,5 to +2,5. This result is in concordance with our hypothesis expecting only few genes dysregulated due to the observation window located 18 weeks before the first clinical sign. Among these genes, about 40% were also up or down regulated in cardiomyopathies or in activation or inhibition of signaling pathways controlling cardiac function.In conclusion, only few genes were both dysregulated in Lmna_K32/+ mice and implicated in other cardiomyopathies suggesting these genes are probably involved in early pathophysiological pathways. Investigation of these pathways may produce new insights in mechanisms leading to cardiomyopathies and may identify new therapeutic targets.
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