Gene expression patterns in transgenic mouse models of hypertrophic cardiomyopathy caused by mutations in myosin regulatory light chain

Abstract

Using microarray and bioinformatics, we examined the gene expression profiles in transgenic mouse hearts expressing mutations in the myosin regulatory light chain shown to cause hypertrophic cardiomyopathy (HCM). We focused on two malignant RLC-mutations, Arginine 58→Glutamine (R58Q) and Aspartic Acid 166 → Valine (D166V), and one benign, Lysine 104 → Glutamic Acid (K104E)-mutation. Datasets of differentially expressed genes for each of three mutants were compared to those observed in wild-type (WT) hearts. The changes in the mutant vs. WT samples were shown as fold-change (FC), with stringency FC ≥ 2. Based on the gene profiles, we have identified the major signaling pathways that underlie the R58Q-, D166V- and K104E-HCM phenotypes. The correlations between different genotypes were also studied using network-based algorithms. Genes with strong correlations were clustered into one group and the central gene networks were identified for each HCM mutant. The overall gene expression patterns in all mutants were distinct from the WT profiles. Both malignant mutations shared certain classes of genes that were up or downregulated, but most similarities were noted between D166V and K104E mice, with R58Q hearts showing a distinct gene expression pattern. Our data suggest that all three HCM mice lead to cardiomyopathy in a mutation-specific manner and thus develop HCM through diverse mechanisms.

Skeletal muscle transcriptome in healthy aging

“…Our analysis also confirmed RNA (ENSG) expression patterns with aging, previously identified in the literature, including FAM83B (Family with Sequence Similarity 83 Member B, involved in hypoxia response 14 ), C12orf75 (chromosome 12 Open Reading Frame 75, implicated in insulin signaling and energy metabolism 15 ), SKAP2 (Src Kinase-Associated Phosphoprotein 2, which regulates sarcomere function 16 ), CRIM1 (Cysteine-Rich Transmembrane Bone Morphogenetic Protein Regulator 1, implicated in smooth muscle contractility 17 ), CFAP61 (Cilia and Flagella-Associated Protein 61, highly abundant in old skeletal muscle 18 ), FEZ2 (Fasciculation and Elongation Protein Zeta 2, participating in fasciculation and axonal elongation 6 ), LGI1 (Leucine-Rich Glioma-Inactivated 1, differentially expressed in frail compared to healthy individuals 18 ), and MYLK4 (Myosin Light Chain Kinase Family Member 4, necessary for contraction, motility, and cell growth 19 – 21 ) mRNAs (Figs. 2a, b and 3a, b , and Supplementary Figs.…”

Regulatory Light Chains in Cardiac Development and Disease

“…In humans, there are a number of RLC missense mutations (i.e., R58Q, D166V, E22K, K104E, D94A, A13T, N47K) that are associated with cardiomyopathies [ 54 , 55 , 56 , 57 , 58 ]. The site of mutation affects the severity of disruption to the cardiomyocytes [ 9 ].…”

Predicted philogeny, secondary conformational structure, and epitope antigenicity of immunological sequences in poultry

“…Instead, gene homology can be found for humans and a lack of mammals contributing to the use of same cell molecular marker in different species (Schulpen et al, 2015). The rodents, such as mice and rat, are important models for several human diseases because they have high gene homology and the results obtained in the rodent models can be extrapolated for humans (Huang et al, 2016). It explains the importance of this study where the molecular markers in poultry are so different from that in a common ancestor and demonstrates no homology between the genes.…”